Embryology - User contributions [en-gb]

File:SensoryDevelopment.pdf

2013-10-10T23:21:48Z

Z3283213:

File:LateDevCNS.pdf

2013-10-10T23:21:27Z

Z3283213:

Lecture - Neural Development

2013-10-10T23:20:34Z

Z3283213:

==Introduction==
[[File:Stage_22_image_217.jpg|thumb|300px|Cerebrum development human embryo (week 8, Stage 22)]]
'''Lecture Date: 2013-10-15 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Ken Ashwell'''

'''The Powerpoint file used to present this lecture is available as a pdf document [[Media:LateDevCNS.pdf‎‎| HERE]]'''

'''A recording of the lecture will be available on Lectopia
[https://secured.learningandteaching.unsw.edu.au/lectopia/lectopiaLogin/default.cfm?ut=153 - Lectopia Login page]'''

The information on this current page is provided only as background.

{{Neural Links}}

{{Neural Links 2}}

==Early Brain Structure==

===Primary Vesicles===
[[Image:CNS primary vesicles.jpg]]

* rostral neural tube forms 3 primary brain vesicles (week 4)
* 3 primary vesicles: '''prosencephalon''' (forebrain), '''mesencephalon''' (midbrain), '''rhombencephalon''' (hindbrain)

===Secondary Vesicles===
[[Image:CNS secondary vesicles.jpg]]

From the 3 primary vesicles developing to form 5 [[S#secondary vesicle|secondary vesicles]]
* prosencephalon- '''telencephalon''' (endbrain, forms cerebral hemispheres), '''diencephalon''' (betweenbrain, forms optic outgrowth)
* '''mesencephalon'''
* rhombencephalon- '''metencephalon''' (behindbrain), '''myelencephalon''' (medullabrain)

==Neural Layers==
===Brain===
{|
| [[File:Stage_22_image_150.jpg|400px]]
| [[File:Stage_22_image_151.jpg|400px]]
|-
| Human Embryo developing head cross section (Week 8, [[Carnegie stage 22|Stage 22]])
| Detail of developing cortex (shown in blue box)
|}

===Spinal Cord===
{|
| [[File:Stage_13_image_057.jpg|400px]]
| [[File:Stage 22 image 176.jpg|400px]]
|-
| Stage 13
| Stage 22
|}

==Fetal Neural==
[[File:Neural-development.jpg|600px]]

Timeline of events in Human Neural Development

[[File:Brain_ventricles_and_ganglia_development_03.jpg|500px]]

[[File:Brain_fissure_development_02.jpg|500px]]

{|
| [[File:Gray0654.jpg|250px]]
| [[File:Gray0655.jpg|250px]]
| [[File:Gray0658.jpg|250px]]
|-
| Human brain at three months (median sagittal section)
| Human brain at four months (inferior surface)
| Human brain at five months (outer surface)
|}
During the fetal period there is ongoing growth in size, weight and surface area of the brain and spinal cord. Microscopically there is ongoing: cell migration, extension of processes, cell death and glial cell development.

Cortical maturation (sulcation and gyration) and vascularization of the lateral surface of the brain starts with the insular cortex (insula, insulary cortex or insular lobe) region during the fetal period. This cerebral cortex region in the adult brain lies deep within the lateral sulcus between the temporal lobe and the parietal lobe.

* '''sulcation''' - The process of brain growth in the second to third trimester which forms sulci, grooves or folds visible on fetal brain surface as gyri grow (gyration). Abnormalities of these processes can lead to a smooth brain (lissencephaly).
* '''gyration''' - The development of surface folds on the brain (singular, gyrus)

Insular Gyral and Sulcal Development

* 13-17 gestational weeks - appearance of the first sulcus
* 18-19 gestational weeks - development of the periinsular sulci
* 20-22 gestational weeks - central sulci and opercularization of the insula
* 24-26 gestational weeks - covering of the posterior insula
* 27-28 gestational weeks - closure of the laeteral sulcus (Sylvian fissure or lateral fissure)

(Data from<ref><pubmed>17962979</pubmed></ref>)

* Between 29-41 weeks volumes of: total brain, cerebral gray matter, unmyelinated white matter, myelinated, and cerebrospinal fluid (from MRI)
** grey matter- mainly neuronal cell bodies; white matter- mainly neural processes and glia.
* total brain tissue volume increased linearly over this period at a rate of 22 ml/week.
* Total grey matter also showed a linear increase in relative intracranial volume of approximately 1.4% or 15 ml/week.
* The rapid increase in total grey matter is mainly due to a fourfold increase in cortical grey matter.
* Quantification of extracerebral and intraventricular CSF was found to change only minimally.

(Text - modified from <ref><pubmed>9485064</pubmed></ref>)

Neural development will continue after birth with substantial glial development, growth, death and reorganization occuring during the postnatally.

:'''Links:''' [[Neural System - Fetal]] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=neurosci&part=A1465&rendertype=figure&id=A1466 Neuroscience - Regional specification of the developing brain]

==Thyroid System and Neural Development==

[[File:Human thyroid system and neural development.jpg|800px]]

Timeline of human thyroid system and brain development from conception to birth.<ref><pubmed>12060827</pubmed></ref> (Estimation of neurogenesis adapted from Bayer et al.<ref><pubmed>8361683</pubmed></ref>)

:'''Links:''' [[Endocrine - Thyroid Development]]

==References==

<references/>

==Movies==

[[Computed Tomography]]

{| border='0px'
|-
| [[File:Mouse_CT_E11.5_movie-icon.jpg|120px|link=Quicktime Movie_-_CT_Mouse_E11.5]]
| [[File:Adult human brain movie icon.jpg|120px|link=Quicktime_Movie_-_Adult_Brain]]
|-
| [[Quicktime Movie_-_CT_Mouse_E11.5|Mouse E11.5 microCT scan]]
| [[Quicktime_Movie_-_Adult_Brain|Human Adult Brain]]
|-
|}

[[Magnetic Resonance Imaging]]

{| border='0px'
|+ '''Human Embryo'''
|-
| [[File:Brain_fissure_development_03.jpg|90px|link=Quicktime Movie - Neural Sylvian Fissure‎‎]]
|-
| [[Quicktime Movie - Neural Sylvian Fissure‎‎|Neural Sylvian Fissure]]
|-
|}

==Historic Embryology==

* [[Book_-_Contributions_to_Embryology_Carnegie_Institution_No.59|Contributions to Embryology Carnegie Institution No.59]] Relative Weight and Volume of the Component Parts of the Brain of the Human Embryo at Different Stages of Development. Jenkins, G.B. (1921). pp5-54.

===Images===
Bailey, F.R. and Miller, A.M. (1921). Text-Book of Embryology. New York: William Wood and Co.

[[Book_-_Text-Book_of_Embryology_17|The nervous system]]

<gallery>
File:Bailey358.jpg|Fig. 358 A two-neurone reflex arc in a Vertebrate
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</gallery>

Gray, Henry. Anatomy of the Human Body. Philadelphia: Lea & Febiger, 1918.

<gallery>
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</gallery>

----

{{2012ANAT2341}}

{{Glossary}}

{{Footer}}

Lecture - Sensory Development

2013-10-10T23:19:12Z

Z3283213:

==Introduction==
[[File:Stage14 sem2cl.jpg|thumb|Human embryo sensory placodes ([[Week 5]], [[Carnegie stage 14|stage 14]])]]
This lecture will introduce development of the special sensory structures associated with hearing, vision, smell and taste. Due to time limitations the lecture will focus on hearing development and if time is available vision and other senses will be introduced in general.

{|
| [[File:Hearing cartoon.jpg|160px|link=Sensory_-_Hearing_and_Balance_Development]]
| [[File:Stage_22_image_153.jpg|160px|link=Sensory_-_Vision_Development]]
| [[File:Stage_22_image_209.jpg|160px|link=Sensory_-_Smell_Development]]
| [[File:Tongue_-_taste_cartoon.jpg|160px|link=Sensory - Taste Development]]
|-
| <center>[[Sensory_-_Hearing_and_Balance_Development|Hearing Development]]</center>
| <center>[[Sensory_-_Vision_Development|Vision Development]]</center>
| <center>[[Sensory_-_Smell_Development|Smell Development]]</center>
| <center>[[Sensory - Taste Development|Taste Development]]</center>
|}

We use the sense of balance and hearing to position ourselves in space, sense our surrounding environment, and to communicate. Portions of the ear appear very early in development as specialized region (otic placode) on the embryo surface that sinks into the mesenchyme to form a vesicle (otic vesicle = otocyst) that form the inner ear.

This region connects centrally to the nervous system and peripherally through specialized bones to the external ear (auricle). This organisation develops different sources forming the 3 ear parts: inner ear (otic placode, otocyst), middle ear (1st pharyngeal pouch and 1st and 2nd arch mesenchyme), and outer ear (1st pharyngeal cleft and 6 surface hillocks).

This complex origin, organisation, and timecourse means that abnormal development of any one system can impact upon the development of hearing.

'''Lecture Date: 2013-09-10 Lecture Time: 16:00 Venue: BioMed E Speaker: Prof. Ken Ashwell'''

'''The Powerpoint file used to present this lecture is available as a pdf document [[Media:SensoryDevelopment.pdf‎‎| HERE]]'''

'''A recording of the lecture will be available on Lectopia
[https://secured.learningandteaching.unsw.edu.au/lectopia/lectopiaLogin/default.cfm?ut=153 - Lectopia Login page]'''

==Textbooks==
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Template:Senses Links}}

{{Template:Hearing Links}}

{{Template:Vision Links}}

{{Template:Taste Links}}

* [[2010_Lecture_17|2010 Lecture]] | [[2009 Lecture 17|2009 Lecture]] | [[BGD_Lecture_-_Face_and_Ear_Development|Medicine Lecture - Face and Ear Development]] | [[BGDB_Practical_-_Face_and_Ear_Development|Medicine Practical - Face and Ear Development]]

|}

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00018-7&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00018-7 Chapter 18 – Development of Eyes and Ears]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10017-X Chapter 17 - Development of the Ears and Eyes]
|}

:'''Links:''' [[Embryology Textbooks]]

==Objectives==
* Understanding of sensory placode development
* Understanding of inner, middle and external ear origins
* Understanding of timecourse of auditory development
* Understanding of abnormalities of auditory development
* Brief understanding of other sensory development

{|
| [[File:Podcast_icon.jpg|link=ANAT2341_Embryology_2011_Lecture_Recordings]]
| '''Lectopia Lecture Audio'''

[[Media:Sensory Lecture 2011.mp3|Sensory Lecture 2011 Audio]]
This was the audio recording I prepared, not the iLecture.
|}

==Development Timing==
[[File:Stage14compare23.jpg|thumb|Comparison of size at stage 14 to 23]]
* '''Week 3''' - otic placode, otic vesicle
* '''Week 5''' - cochlear part of otic vesicle elongates (humans 2.5 turns)
* '''Week 9''' - Mesenchyme surrounding membranous labryinth (otic capsule) chondrifies
* '''Week 12-16''' - Capsule adjacent to membranous labryinth undegoes vacuolization to form a cavity (perilymphatic space) around membranous labrynth and fills with perilymph
* '''Week 16-24''' - Centres of ossification appear in remaining cartilage of otic capsule form petrous portion of temporal bone. Continues to ossify to form mastoid process of temporal bone.
* '''3rd Trimester''' - Vibration acoustically of maternal abdominal wall induces startle response in fetus.

==Embryonic Origin Overview==
[[File:Adult hearing embryonic origins.jpg|thumb|300px|Adult hearing embryonic origins]]
'''External Ear'''

* Auricle - Pharyngeal Arches 1 and 2 (ectoderm, mesoderm)
* External Auditory Meatus - Pharyngeal Arch 1 groove or cleft (ectoderm)
* Tympanic Membrane - Pharyngeal Arch 1 membrane (ectoderm, mesoderm, endoderm)

'''Middle Ear'''

* Middle Ear Ossicles
** Malleus and incus - Pharyngeal Arch 1 cartilage Neural crest (ectoderm)
** Stapes - Pharyngeal Arch 2 cartilage Neural crest (ectoderm)
* Middle Ear Muscles
** Tensor tympani - Pharyngeal Arch 1 (mesoderm)
** Stapedius - Pharyngeal Arch 2 (mesoderm)
* Middle ear cavity - Pharyngeal Arch 1 pouch (endoderm)

'''Inner Ear'''

* Inner Ear Labyrinth
** Cochlea - Otic vesicle - Otic placode (ectoderm)
** Semicircular canals - Otic vesicle - Otic placode (ectoderm)
** Saccule and utricle - Otic vesicle - Otic placode (ectoderm)
* Cranial Nerve VIII
** Auditory component - Otic vesicle and neural crest (ectoderm)
** Vestibular component - Otic vesicle and neural crest (ectoderm)

== Sensory Placodes ==
[[File:Stage11_sem20a.jpg|thumb|Otic placodes ([[Carnegie_stage_11|Stage 11]] dorsal view)]]
[[File:Stage14 sem2b-limb.jpg|thumb|Stage 14 sensory placodes]]
* week 4 a series of thickened surface ectodermal patches form in pairs in the head region.
** Recent research suggests that all sensory placodes may arise from common panplacodal primordium origin around the neural plate, and then differentiate to eventually have different developmental fates. PMID 20801420

* sensory placodes will later contribute key components of each of our special senses (vision, hearing and smell).
* Other species have a number of additional placodes which form other sensory structures (fish, lateral line receptor).
* Note that their initial postion on the developing head is significantly different to their final position in the future sensory system.

===Otic Placode===

* stage 13/14 embryo (shown below) the otic placode has sunk from the surface ectoderm to form a hollow epithelial ball, the otocyst, which now lies beneath the surface surrounded by mesenchyme (mesoderm).
* The epithelia of this ball varies in thickness and has begun to distort, it will eventually form the inner ear membranous labyrinth.

===Lens Placode===

* lies on the surface, adjacent to the outpocketing of the nervous system (which will for the retina) and will form the lens.

===Nasal Placode===

* 2 components (medial and lateral) and will form the nose olefactory epithelium.

:'''Links:''' [[Placodes]]

==Inner Ear==
[[File:Stage13 otocyst.jpg|thumb|Stage 13 otocyst]]
[[File:Stage22 ear.jpg|thumb|Stage 22 ear]]

* The inner ear is derived from a pair of surface sensory placodes (otic placodes) in the head region.
* These placodes fold inwards forming a depression, then pinch off entirely from the surface forming a fluid-filled sac or vesicle (otic vesicle, otocyst).
* The vesicle sinks into the head mesenchyme some of which closely surrounds the otocyst forming the otic capsule.
* The otocyst finally lies close to the early developing hindbrain (rhombencephalon) and the developing vestibulo-cochlear-facial ganglion complex.

:'''Links:''' [[Hearing - Inner Ear Development|Inner Ear]] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.894 Neuroscience - The Inner Ear]
==Middle Ear==
[[File:Pharyngeal arch cartilages.jpg|thumb|Pharyngeal arch cartilages]]
* The middle ear ossicles (bones) are derived from 1st and 2nd arch mesenchyme.
* The space in which these bones sit is derived from the 1st pharyngeal pouch.
** remains connected to the oral cavity by the auditory tube.

:'''Links:''' [[Hearing - Middle Ear Development|Middle Ear]] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.893 Neuroscience - The Middle Ear]
==Outer Ear==
[[File:External ear stages-14-23-adult.jpg|thumb|External ear stages 14-23 and adult (not to scale)]]
* The external ear is derived from 6 surface hillocks, 3 on each of pharyngeal arch 1 and 2.
* The external auditory meatus is derived from the 1st pharyngeal cleft.
* The newborn external ear structure and position is an easily accessible diagnostic tool for potential abnormalities or further clinical screening.

===Pinna- Auricle===
[[File:Streeter1922-plate01.jpg|thumb|arch 1 and 2 hillocks]]
* develops from six aural hillocks
* 3 on first arch
* 3 on second arch
* originally on neck, moves cranially during mandible development

{| class="prettytable"
| Pharyngeal Arch
| Hillock
| Auricle Component

|-
| Arch 1
| 1
| tragus

|-
|
| 2
| helix

|-
|
| 3
| cymba concha

|-
| Arch 2
| 4
| concha

|-
|
| 5
| antihelix

|-
|
| 6
| antitragus

|}

* Outer- external auditory meatus

* derived from first pharyngeal cleft
* ectodermal diverticulum
* week 5 - extends inwards to pharynx
* until week 18 has ectodermal plug - plug forms stratified squamous epithelia of canal and outer eardrum

'''Timeline'''
{|
|
* Embryonic Period - Ectodermal cells proliferate and fill the entire lumen forming a meatal plug
* 10 weeks - Meatal plug extends in a disc-like fashion. In the horizontal plane the meatus is boot-shaped with a narrow neck and the sole of the meatal plug spreading widely to form the future tympanic membrane medially. Proximal portion of the neck starts to be resorbed.
* 13 weeks - Disc-like plug innermost surface in contact with the primordial malleus, contributes to the formation of the tympanic membrane.
* 16.5 week - Meatus is fully patent throughout its length, lumen is still narrow and curved.
* 18 week - Meatus is already fully expanded to its complete form.

(EAM data - Nishimura, 1992 PMID 1441991)
| [[File:Gray0908.jpg|300px]]

outer ear and external auditory meatus
|}
'''Links:''' [[Hearing - Outer Ear Development|Outer Ear]] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.891 Neuroscience - The External Ear]

== Middle ==

===tympanic cavity===

* derived from first pharyngeal pouch
* extends as tubotympanic recess - during week 5 recess contacts outer ear canal
* mesoderm between 2 canals forms tympanic membrane
* expands to form tympanic recess
* stalk of recess forms auditory tube(eustachian tube, pharyngotympanic tube)

===Ossicles===
[[File:Pharyngeal arch cartilages.jpg|thumb|Pharyngeal arch cartilages]]
* develop from first and second pharyngeal arches
* tympanic cavity enlarges to incorporate
* coats with epithelia

* first arch mesoderm

* tensor tympani muscle
* malleus and incus

* second arch mesoderm

* stapedius muscle and stapes

Middle Ear Genes - gooscoid, RARs, Prx1, Otx2, Hoxa1, Hoxb1, endothelian related molecules

==Inner==
[[File:Stage11_sem20a.jpg|thumb|Otic placodes ([[Carnegie_stage_11|Stage 11]] dorsal view)]]
===Otocyst===
[[File:Stage12 sem1.jpg|thumb|Carnegie Stage 12 otic placode]]
[[File:Stage13_sem2c.jpg|thumb|Carnegie Stage 13 otic vesicle]]
<gallery>
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File:Stage_22_image_218.jpg|Week 8 cochlea
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</gallery>
* week 3 otic placode forms on surface ectoderm
* otic placode sinks into mesoderm
* forms otocyst (otic vesicle)
* branches form and generate endolymphatic duct and sac
* forms vestibular (dorsal) and cochlear (ventral) regions
* differentiation of otic vesicle to membranous labyrinth

===Vestibular Sac ===

* generates 3 expansions - form semicircular ducts
* remainder forms utricle
* epithelia lining generates - hair cells, ampullary cristae, utricular macula
* Vestibular - Otoconia, otoconin- inner ear biominerals

===Cochlear sac===
{|
|
* generates coiled cochlear duct (humans 2 1/2 turns)
* remainder forms saccule
* epithelia lining generates
* hair cells
* structures of organ of corti
* saccular macula
| [[File:Stage_22_image_218.jpg|400px]]
|}

[[File:Inner ear haircells.jpg|thumb|Inner ear hair cells]]

===Bony Labyrinth===

* formed from chrondified mesoderm
* Periotic Capsule
* mesenchyme within capsule degenerates to form space filled with perilymph

===Vestibulocochlear Nerve===

* forms beside otocyst
* from wall of otocyst and neural crest cells
* bipolar neurons
* vestibular neurons
** outer end of internal acoustic meatus
** innervate hair cells in membranous labyrinth
** axons project to brain stem and synapse in vestibular nucleus
* cochlear neurons
** cell bodies lie in modiolus
** central pillar of cochlear
** innervate hair cells of spiral organ
** axons project to cochlear nucleus

Inner Ear Genes

* hindbrain segmentation occurs at same time placode arises
* otocyst adjacent to rhombomere 5
* may influence development
* Hoxa1, kreisler, Fgf3
* genes regulating neural crest cells (neural genes)
* Pax2 Ko affects cochlear and spiral ganglion, but not vestibular apparatus
* nerogenin 1 affects both ganglia

===Semicircular canal ===

* Otx1- cochlear and vestibular normal

* Hmx3, Prx1, Prx2

Sensory Organs

* thyroid hormone receptor beta
* Zebrafish-mindbomb mutant has excess hair cells but not supporting cells, Notch-Delta signaling

* Gene Expression-inner ear

* Brn-3c and Hair cell development
* Supporting Cells- p27kip
* Thyroid Hormone
* Ganglion neurons require growth factors
* vestibular neurons- BDNF, NT3
** survival not development

==Postnatal Changes==
[[Image:Eustacian tube angle.jpg|thumb|Eustacian tube angle changes]]
Newborn to adult Eustachian (auditory, otopharyngeal or pharyngotympanic) tube.
* Connects middle ear cavity to nasopharynx portion of pharynx

===Functions===
* Ventilation - pressure equalization in the middle ear
* Clearance - allow fluid drainage from the middle ear Tube is normally closed and opened by muscles

At birth
* shorter (17-18 mm), narrower and runs almost horizontal Tube is opened by a single muscle, tensor palati muscle

Adult
* longer (twice as long), wider and runs at approximately 45 degrees to the horizontal. Tube is opened by two separate muscles, tensor palati and levator palati

==Vision==

===Timeline===

* '''Weeks 3-4''' - Eye Fields-Optic Vesicle
* '''Weeks 5-6''' - Optic Cup, Lens Vesicle, Choroid Fissure, Hyaloid Artery
* '''Weeks 7-8''' - Cornea, Anterior Chamber, Pupillary Membrane, Lens, Retina
* '''Weeks 9-15''' - Iris, Ciliary Body
* '''Weeks 8-10''' - Eyelids

===Stage 13 (week 5)===

{|
| [[File:Stage 13 image 057.jpg|120px]]
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| [[:File:Stage 13 image 057.jpg|B1L]]
| [[:File:Stage 13 image 058.jpg|B2L]]
| [[:File:Stage 13 image 059.jpg|B3L]]
| [[:File:Stage 13 image 060.jpg|B4L]]
| [[:File:Stage 13 image 061.jpg|B5L]]
| [[:File:Stage 13 image 062.jpg|B6L]]
| [[:File:Stage 13 image 063.jpg|B7L]]
|}

===Lens===

Surface ectoderm -> lens placode (optic placode) -> lens pit -> lens vesicle -> lens fibres -> lens capsule and embryonic/fetal nucleus.

===Retina===

Neural plate ectoderm -> prosencephalon (forebrain) eye fields -> neural plate growth carries eye field region forward -> eye field invaginates forming optic grooves (sulci) -> diencephalon optic groove interacts with surface ectoderm (induces optic placode) -> optic stalk -> optic vesicle -> folds inward (optic cup) forming double layer -> inner neural retina, outer pigmented retina

Links: [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm Embryo Images - Eye Development]

===Neural Crest===

Eye connective tissue

==Abnormalities==
[[File:Hearing-vestibular sac abnormality.jpg|thumb|vestibular sac abnormality]]
* Inner - common cavity, severe cochlear hypoplasia
** Large vestibular aqueduct syndrome (LVAS) can be one of the common causes of hearing loss
* Middle - rare and can be part of first arch syndrome, Malleus, Incus and Stapes Fixation
** Cholesteatoma- Epithelium trapped within skull base in development, erosion of bones: temporal bone, middle ear, mastoid
* Outer - Several genetic effects and syndromes, Environmental Effects

Outer Ear Abnormalities
[[File:Microtia.jpg|thumb|Microtia]]
[[File:Preauricular sinus.jpg|thumb|Preauricular sinus]]
* Microtia - abnormally small external ear
* Preauricular sinus - occurs in 0.25% births, bilateral (hereditary) 25-50%, unilateral (mainly the left), duct runs inward can extend into the parotid gland, Postnatally sites for infection

Fetal Alcohol Syndrome
[[File:FASface.jpg|thumb|Fetal Alcohol Syndrome Face]]
* Postion- Lower or uneven height, "railroad track” appearance, curve at top part of outer ear is under-developed, folded over parallel to curve beneath

=== Congenital Deafness ===
'''Sensorineural''' - cochlear or central auditory pathway

* Hereditary
* recessive- severe
* dominant- mild
** can be associated with abnormal pigmentation (hair and irises)

* Acquired
** rubella (German measles), maternal infection during 2nd month of pregnancy, vaccination of young girls
** streptomycin
** antibiotic
** thalidomide

'''Conductive '''- disease of outer and middle ear
[[File:Eustacian_tube_angle.jpg|thumb|Eustacian tube angle]]

* produced by otitis media with effusion, is widespread in young children.
* temporary blockage of outer or middle ear

==Bionic Ear==
Cochlear Implant - Professor Graeme Clark (1960s, Australia) Array of electrodes implanted within cochlea, direct electrical stimulation to auditory nerve fibres

== Conductive Hearing Loss ==
* Conductive Hearing Loss Produces a Reversible Binaural Hearing Impairment David R. Moore, Jemma E. Hine, Ze Dong Jiang, Hiroaki Matsuda, Carl H. Parsons, and Andrew J. King J. Neurosci. 1999;19 8704-8711 [http://www.jneurosci.org/cgi/content/abstract/19/19/8704 http://www.jneurosci.org/cgi/content/abstract/19/19/8704]
** tested ferrets by lon-term plugging of ear canal
** Repeated testing during the 22 months after unplugging revealed a gradual return to normal levels of unmasking.
** Results show that a unilateral conductive hearing loss, in either infancy or adulthood, impairs binaural hearing both during and after the hearing loss.
** Show scant evidence for adaptation to the plug and demonstrate a recovery from the impairment that occurs over a period of several months after restoration of normal peripheral function.

== References ==
===Textbooks===
* '''Before We Are Born''' (5th ed.) Moore and Persaud Chapter 20: p460-479
* '''Essentials of Human Embryology''', Larson Chapter 12: p252-272

===Online Textbooks===
* '''Developmental Biology''' (6th ed.) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.figgrp.5455%20 Evolution of the mammalian middle ear bones from the reptilian jaw] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.figgrp.5460 Chick embryo rhombomere neural crest cells] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.table.3135 Some derivatives of the pharyngeal arches] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2871 Formation of the Neural Tube] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2884 Differentiation of the Neural Tube] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2894 Tissue Architecture of the Central Nervous System] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2908 Neuronal Types] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2937 Snapshot Summary: Central Nervous System and Epidermis]

* '''Neuroscience''' Purves, Dale; Augustine, George J.; Fitzpatrick, David; Katz, Lawrence C.; LaMantia, Anthony-Samuel; McNamara, James O.; Williams, S. Mark. Sunderland (MA): Sinauer Associates, Inc. ; c2001 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.879 The Auditory System] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.894 The Inner Ear] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.893 The Middle Ear] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.891 The External Ear] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.1447 Early Brain Development] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.1546 Construction of Neural Circuits] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.1640 Modification of Brain Circuits as a Result of Experience]

* '''Molecular Biology of the Cell''' (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002. [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.section.3963 Neural Development] | [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.figgrp.3966 The three phases of neural development]

* '''Clinical Methods''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.1949 63. Cranial Nerves IX and X: The Glossopharyngeal and Vagus Nerves] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3847 The Tongue] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3777 126. The Ear and Auditory System] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3627#3654 An Overview of the Head and Neck - Ears and Hearing] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3897 Audiometry]

* '''Health Services/Technology Assessment Text (HSTAT)''' Bethesda (MD): National Library of Medicine (US), 2003 Oct. [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=hstat1a.section.25014#25029 Developmental Disorders Associated with Failure to Thrive]

* '''Eurekah Bioscience Collection'''[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.chapter.53006 Cranial Neural Crest and Development of the Head Skeleton]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=hearing+development hearing development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=hearing+development hearing development]

==External Links==

{{External Links}}

* NIDCD - [http://www.nidcd.nih.gov/health/balance/balance_disorders.asp Balance Disorders]
* [http://www.med.unc.edu/embryo_images/ Embryo Images Online]
** '''Eye Development''' - [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm Eye Development Unit] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye001.htm Eye Fields-Optic Vesicle (Weeks 3-4)] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye009.htm Optic Cup, Lens Vesicle, Choroid Fissure, Hyaloid Artery (Weeks 5-6)] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye016.htm Cornea, Anterior Chamber, Pupillary Membrane, Lens, Retina (Weeks 7-8)] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye022.htm Iris, Cilliary Body (Weeks 9-15)] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye025.htm Eyelids (Weeks 8-10)]
** '''Ear Development''' - [http://www.med.unc.edu/embryo_images/unit-ear/ear_htms/eartoc.htm Ear Development Unit] | [http://www.med.unc.edu/embryo_images/unit-ear/ear_htms/ear001.htm Inner Ear | [http://www.med.unc.edu/embryo_images/unit-ear/ear_htms/ear012.htm Middle Ear] | [http://www.med.unc.edu/embryo_images/unit-ear/ear_htms/ear014.htm External Ear]

== Terms ==
* '''altricial animal''' - Term used to describe an animal born in a helpless state, with incomplete development of sensory systems at birth. For example rats and mice are born with incomplete development of visual and auditory systems.
* '''ampulla''' - Term used to describe an anatomical dilation of a tube or canal lumen. Anatomical description of the opening end of the uterine tube lying above the ovary and the enlarged initial segmeny of the semicircular canals of the inner ear vestibular system. (More? [ear6.htm Inner Ear] | [genitalXXuterus.htm Genital System - Female Uterus])
* '''aneurism''' - (Greek, ''aneurysma'' = a widening, aneurysm) A term used to describe an abnormal widening of a vessel or anatomical tubal structure.
* '''aquaeductus vestibuli '''- see vestibular aqueduct
* '''auditory neuropathy''' - (AN) abnormality of transmission of sound information to the brain.
* '''auditory tube '''- (eustachian tube) between the middle ear and oral cavity, has a bony (tympanic 1/3) and cartilaginous (pharyngeal 2/3) portion. The main role is equalization of pressure and fluid drainage in the middle ear.
* '''auricular hillock '''- see hillock
* '''atresia''' - narrowing, usually of an anatomical tube or cavity.
* '''autophagocytosis''' - (Greek, auto = self, phagy = eating, also called autophagy) a cell death mechanism that uses the cell's own lysosomes to self digest.
* '''border cells''' - columnar cells within the organ of Corti on the medial portion of the basilar membrane.
* '''canalis reuniens''' - (ductus reuniens, canaliculus reuniens, canalis reuniens, Hensen's canal, Hensen's duct, uniting canal, canalis reuniens of Hensen) short narrow canal connecting the cochlea duct to the saccule. (Victor Hensen, 1835-1924)
* '''cerumen''' - (ear wax) produced by glands in the skin of the outer portion of the ear canal.
* '''chondrified''' - the developmental differentiation of cartilage from mesenchye, an embryonic connective tissue.
* '''cristae ampullaris''' - located in the ampulla of the membranous semicircular canals a region with both supporting and hair cells. The hair cell cilia are embedded in the gelatinous cupula.
* '''claudius cells '''- (cells of Claudius) columnar cells with microvilli overlying the basilar membrane and extend from Hensen's cells to the spiral prominence. Barrier cells that lie external to the organ of corti in endolymph.
* '''cochlear sac '''- embryonic structure, which will form the coiled cochlear duct and contribute to the saccule.
* '''cochlear aqueduct''' - a bony channel containing the fibrous periotic duct. It connects the basal turn of the cochlea perilymphatic space with the subarachnoid space of the posterior cranial cavity.
* '''cochlin''' - major constituent of the inner ear extracellular matrix.
* '''collagen type II''' - major constituent of the inner ear extracellular matrix.
* '''conductive loss''' - term used to describe one of the two major classes of hearing loss involving external and middle ear abnormalities (other form is Sensorineural loss).
* '''connexins '''- channel proteins of the gap junctions that allow rapid communication between adjacent cells. The two connexins Cx26 and Cx30 are the major proteins of cochlear gap junctions.
* '''connexin 26''' - A strikingly high proportion (50%) of congenital bilateral nonsyndromic sensorineural deafness cases have been linked to mutations in the GJB2 coding for the connexin26
* '''cupular deposits''' - basophilic material on the cupulae of the semicircular ducts, an postnatal ageing phenomenon seen in some vestibular labyrinth.
* '''clinical weeks''' - taken from last menstrual period (LMP) and therefore approximately two weeks before fertilization occurs.
* Deiters' cells
* '''discoidin domain receptor 1''' - (DDR1) a tyrosine kinase receptor activated by native collagen, expressed in the basement membrane and with fibrillar collagens. Found in basal cells of the stria vascularis, type III fibrocytes, and cells lining the basilar membrane of the organ of Corti. {Meyer zum Gottesberge, 2008 #1877}
* ductus utriculosaccularis -
* '''endochondral ossification''' - the process of bone formation from a pre-existing cartilage template.
* endolymphatic fluid -
* '''endolymphatic sac''' - inner ear structure that has anatomically both an intraosseous and extraosseous component. Th e sac has functions regulating endolymph that are both secretory and absorptive. Also the site of endolymphatic sac tumors either sporadical occurring or associated with the autosomal-dominant von Hippel-Lindau (VHL) disease, due to a germ line mutation.
* '''embryological weeks''' - taken from the time of fertilization which typically occurs around the middle (day 14), or just after, of the typical 28 day menstrual cycle.
* '''Emx2''' - homeobox gene affecting middle ear and inner ear development.
* '''eustachian tube''' - (auditory tube) A cavity linking the pharynx to the middle ear, which develops from the first pharyngeal pouch. Named after Bartolomeo Eustachi (1500 - 1574) an Italian anatomist. Several functions including the equalization of pressure in the middle ear.
* '''external auditory meatus''' - (ear canal) develops from the first pharyngeal cleft.
* '''ear wax '''- see cerumen.
* '''espins''' - calcium-resistant actin-bundling proteins enriched in hair cell stereocilia and sensory cell microvilli and spiral ganglion neurons (SGNs)
* external auditory canal -
* '''fenestra ovalis''' - (oval window) separates the tympanic cavity from the vestibule of the osseous labyrinth.
* '''fenestra rotunda''' - (round window) separates the tympanic cavity from the scala tympani of the cochlea.
* '''fetus''' - (foetus) term used to describe human development after the 8th week (10th clinical week, LPM) and covers the developmental periods of second and third trimester.
* '''fibroblast growth factor 1''' - (Fgf-1) a growth factor released from cochlea sensory epithelium which stimulates spiral ganglion neurite branching.
* '''fibroblast growth factor 8''' - (Fgf-8) a growth factor released by inner hair cells which regulates pillar cell number, position and rate of development.
* '''fibroblast growth factor receptor 3''' - (Fgfr-3) a tyrosine kinase receptor with a role in the commitment, differentiation and position of pillar cells in the organ of corti
* '''fundamental frequency''' - (natural frequency) the lowest frequency in a harmonic series, for the female voice this is about 225 Hz.
* '''helicotrema''' - term used to describe the cochlear apex.
* Hes - (hairy and enhancer of split) family of factors, which has been shown to be a general negative regulator of neurogenesis (Zheng, 2000).
* '''hillock''' - a small hill, used to describe the six surface elevations on pharyngeal arch one and two.
* Hindbrain - Invaginate -
* '''Incus''' - (anvil) auditory ossicle
* inner phalangeal cells
* '''inner pillar cells''' - organ of Corti cells arranged in rows and form a boundary between the single row of inner hair cells and three rows of outer hair cells. These cells have surface-associated microtubule bundles.
* inner sulcus - area of the cochlear duct
* interdental region -
* '''internal auditory meatus''' - (internal acoustic meatus, IAM) Anatomical canal in which CN VII and CN VIII ganglia reside and pass through to the brainstem. This bony canal lies between the posterior surface of the petrous pyramid and the bony labyrinth within the dense petrous bone. Also associated clinically with the site where acoustic neuromas may occur.
* '''Kolliker's organ''' - (Kollicker's organ, greater epithelial ridge) Developing cochlear structure consisting of columnar-shaped supporting cells filling the inner sulcus and lying directly under the tectorial membrane. This transient organ regresses and generates the space of the inner sulcus. Rudolph Albert von Kolliker (1817-1905)??
* lateral semicircular duct -
* Limbus -
* '''LMP''' - acronym for last menstrual period, used to clinically measure gestation.
* '''malleus''' - (hammer) auditory ossicle
* '''mastoid process''' - of temporal bone
* '''Math1''' - homolog of the Drosophila proneural gene atonal, necessary and sufficient for the production of hair cells in the mouse inner ear. {Chen, 2002 #1932}Negatively regulated by Hes1 and Hes5
* '''meatal plug''' - temporary blockage of the external auditory meatus which forms at the end of the embryonic period and remains present until the seventh month.
* '''meatus''' - anatomical opening, cavity or space (external acoustic meatus,internal auditory meatus)
* '''Meckel's cartilage''' - first pharyngeal ach cartilage, located within the mandibular prominence. This cartilage first appears at stage 16, stage 20 the beginning of membranous ossification. Named after Johann Friedrich Meckel, (1781 - 1833) a German anatomist. (http://www.whonamedit.com/doctor.cfm/1840.html)
* membranous labyrinth - Mesenchyme - Mesoderm - Microtia - Modiolus -
* '''mucopolysaccharidosis''' - (MPS IIIB, Sanfilippo Syndrome type B) abnormality caused by a deficiency in the lysosomal enzyme N-acetyl-glucosaminidase (Naglu). Children with MPS IIIB develop abnormal hearing, and mental functioning culminating in early death.
* '''netrin-1''' - secreted growth factor, expressed in the organ of Corti and spiral ganglion cells, role in process outgrowth.
* neural tube -
* '''olivocochlear''' - brainstem cholinergic and GABAergic efferent system that innervates sensory cells and sensory neurons of the inner ear.
* organ of Corti - organ of Corti protein II - (OCP-II) cytosolic protein or transcription factor?
* '''otolithic membrane''' - extracellular matrix that cover the sensory epithelia of the inner ear.
* '''ossicle''' - (small bone) the individual bone of the three middle ear bones (auditory ossicles), which reduce vibrational amplitude but increase force to drive fluid-filled inner ear.
* ossify - the process of bone formation.
* otic capsule -
* otic cup
* otic placode -
* otic vesicle -
* '''otoconin''' - inner ear biominerals required for vestibular apparatus function.
* '''otogelin''' - (Otog) an inner ear specific glycoprotein expressed in cochlea cells at different developmental times.
* '''otolithic membrane''' - a membrane within the utricle and saccule containing embedded hair cell cilia and small crystalline bodies of calcium carbonate (otoliths). Functions to detect head motion.
* '''otoliths''' - small crystalline bodies of calcium carbonate found within the otolitic membrane of the utricle and saccule.
* '''ototoxic''' - compound or drug causing temporary or permanent hearing loss.
* '''outer hair cells''' - (OHCs) three rows of hair cells that function to increase basilar membrane motion through a local mechanical feedback process within the cochlea, the "cochlear amplifier".
* '''outer pillar cells''' - arranged in rows and form a boundary between the single row of inner hair cells and three rows of outer hair cells.
* '''paratubal musculature''' - muscles lying beside the auditory (Eustachian) tube. The tensor veli, palatini (TVP) and tensor tympani muscles.
* perilymph - perilymphatic space - Periotic Capsule - petrous portion - of temporal bone
* '''pejvakin gene''' - in humans, two missense mutations in this gene cause nonsyndromic recessive deafness (DFNB59) by affecting the function of auditory neurons.
* pharyngeal archpharyngeal pouchpharyngeal membranePharynx
* '''pillar cells''' - (PC) form an inner and outer row of support cells that form a boundary between inner and outer hair cells.
* Placode
* '''preyer reflex''' - ear flick in mouse in response to sound.
* presbyacusis
* '''prestin''' - a motor protein structurally similar to the anion transporter family expressed in cochlear outer hair cells.
* '''preauricular tag''' - skin tags located in front of the external ear opening, are common in neonates and in most cases are normal, though in some cases are indicative of other associated abnormalities.
* primordium-
* '''protocadherin 15''' - (Pcdh15) required for initial formation of stereocilia bundles and changes in the actin meshwork within hair cells. The Ames waltzer (av) mouse mutant has both auditory and vestibular abnormalities from a mutation in this gene.
* '''Reichert's cartilage''' - pharyngeal ach 2 cartilage, named after Karl Bogislaus Reichert (1811 - 1883) a German anatomist.
* '''Reissner's membrane''' - (vestibular membrane, vestibular wall) is a membrane located inside the cochlea separating the scala media from scala vestibuli. Named after Ernst Reissner (1824-1878) a German anatomist. ‚ÄúIt primarily functions as a diffusion barrier, allowing nutrients to travel from the perilymph to the endolymph of the membranous labyrinth.
* rhombomere -
* Saccular macula -
* Saccule - (Latin, sacculus = a small pouch)
* sacculocollic reflex -
* scala tympani - one of the three Cochlea cavities, it is filled with perilymph.
* '''Scarpa's ganglion''' - (vestibular ganglion) primary afferent vestibular neuron ganglion of the vestibular nerve. Located within the internal auditory meatus.
* '''semicircular canals''' - series of fluid-filled loops of the inner ear required for balance and sensing acceleration.
* sensorineural - term used to describe one of the two major classes of hearing loss involving the central pathway from the cochlear (other form is conductive loss).
* '''space of Nuel''' - within the cochlea, an organ of Corti space between the outer pillar cells and the phalangeal and hair cells. Named after Jean-Pierre Nuel (1847-1920) a Belgian ophthalmologist.
* '''spiral ganglion neurons''' - (SGN) innervate the inner (Type I) and outer (Type II) hair cells of the cochlea.
* '''stapedius muscle''' - (innervated by CN VII tympanic branch) one of the two muscles in the middle ear, contraction of this muscle pulls the stapes and dampens auditory ossicle movement.
* '''stapes''' - (stirrup) a middle ear auditory ossicle (bone).stapes footplate - startle response -
* '''stereocilia''' -finger-like projections from the apical surface of sensory hair cells forming the hair bundle in the cochlea. Formed by tightly cross-linked parallel actin filaments in a paracrystalline array with cell surface specializations (tip links, horizontal top connectors, and tectorial membrane attachment crowns).
* '''stratified squamous epithelia''' - classification of epithelium which transiently forms a plug in external ear canal to the outer eardrum.
* '''stria vascularis''' - forms the outer wall of the cochlear duct of the mammalian cochlea is composed primarily of three types of cells. Marginal cells line the lumen of the cochlear duct and are of epithelial origin. Basal cells also form a continuous layer and they may be mesodermal or derived from the neural crest. Intermediate cells are melanocyte-like cells, presumably derived from the neural crest, and are scattered between the marginal and basal cell layers. The stria forms endolymph and also contains a rich supply of blood vessels.
* sulcus -
* '''synostotically''' - anatomically normally separate skeletal bones fused together.
* '''tectorial membrane''' - extracellular matrix that cover the sensory epithelial hair cells of the organ of corti within the cochlea.
* '''alpha-tectorin and beta'''- (TECTA, TECTB) major non-collagenous protein component of the tectorial membrane forming a striated-sheet matrix. Synthesized as glycosylphosphatidylinositol-linked, membrane bound precursors.
* temporal bone -
* '''tensor tympani '''- (innervated by CN V mandibular nerve) one of the two muscles in the middle ear, contraction of this muscle pulls the malleus and tenses the tympanic membrane, dampening auditory ossicle movement. The muscle arises from auditory tube (cartilaginous portion) and is inserted into the malleus (manubrium near the root).
* teratogens - trilaminar embryo -
* '''tonotopy''' - term describing the mapping along the tectorial membrane within the cochlea of the different sound frequencies.
* tympanic cavity - tympanic membrane -Utricle -Vacuolization - Vesicle - vestibular apparatus - vestibular evoked myogenic potential (VEMP) test
* '''vestibular ganglion''' - (Scarpa's ganglion) primary afferent vestibular neuron ganglion of the vestibular nerve. Located within the internal auditory meatus.
* '''vestibular membrane''' - (Reissner's) extends from the spiral lamina to the outer wall and divides the cochlea into an upper scala vestibuli, a lower scala tympani.
* '''Vestibulocochlear Nerve''' - Cranial Nerve VIII
* '''Whirlin''' - A PDZ scaffold protein expressed in hair cells at the stereocilia tips, essential for the stereocilia elongation process. The DFNB31 gene mutations cause hearing loss in human and mouse. This protein can interact with membrane-associated guanylate kinase (MAGUK) protein, erythrocyte protein p55 (p55).
* '''Wnt7a''' - signaling through the Wnt pathway regulates the development of hair cell unidirectional stereociliary bundle orientation.

[[Category:Senses]] [[Category:Hearing]]

----

{{2012ANAT2341}}

Lecture - Sensory Development

2013-10-10T23:18:13Z

Z3283213:

==Introduction==
[[File:Stage14 sem2cl.jpg|thumb|Human embryo sensory placodes ([[Week 5]], [[Carnegie stage 14|stage 14]])]]
This lecture will introduce development of the special sensory structures associated with hearing, vision, smell and taste. Due to time limitations the lecture will focus on hearing development and if time is available vision and other senses will be introduced in general.

{|
| [[File:Hearing cartoon.jpg|160px|link=Sensory_-_Hearing_and_Balance_Development]]
| [[File:Stage_22_image_153.jpg|160px|link=Sensory_-_Vision_Development]]
| [[File:Stage_22_image_209.jpg|160px|link=Sensory_-_Smell_Development]]
| [[File:Tongue_-_taste_cartoon.jpg|160px|link=Sensory - Taste Development]]
|-
| <center>[[Sensory_-_Hearing_and_Balance_Development|Hearing Development]]</center>
| <center>[[Sensory_-_Vision_Development|Vision Development]]</center>
| <center>[[Sensory_-_Smell_Development|Smell Development]]</center>
| <center>[[Sensory - Taste Development|Taste Development]]</center>
|}

We use the sense of balance and hearing to position ourselves in space, sense our surrounding environment, and to communicate. Portions of the ear appear very early in development as specialized region (otic placode) on the embryo surface that sinks into the mesenchyme to form a vesicle (otic vesicle = otocyst) that form the inner ear.

This region connects centrally to the nervous system and peripherally through specialized bones to the external ear (auricle). This organisation develops different sources forming the 3 ear parts: inner ear (otic placode, otocyst), middle ear (1st pharyngeal pouch and 1st and 2nd arch mesenchyme), and outer ear (1st pharyngeal cleft and 6 surface hillocks).

This complex origin, organisation, and timecourse means that abnormal development of any one system can impact upon the development of hearing.

{|
'''Lecture Date: 2013-09-10 Lecture Time: 16:00 Venue: BioMed E Speaker: Prof. Ken Ashwell'''

'''The Powerpoint file used to present this lecture is available as a pdf document [[Media:SensoryDevelopment.pdf‎‎| HERE]]'''

'''A recording of the lecture will be available on Lectopia
[https://secured.learningandteaching.unsw.edu.au/lectopia/lectopiaLogin/default.cfm?ut=153 - Lectopia Login page]'''

|}

==Textbooks==
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Template:Senses Links}}

{{Template:Hearing Links}}

{{Template:Vision Links}}

{{Template:Taste Links}}

* [[2010_Lecture_17|2010 Lecture]] | [[2009 Lecture 17|2009 Lecture]] | [[BGD_Lecture_-_Face_and_Ear_Development|Medicine Lecture - Face and Ear Development]] | [[BGDB_Practical_-_Face_and_Ear_Development|Medicine Practical - Face and Ear Development]]

|}

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00018-7&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00018-7 Chapter 18 – Development of Eyes and Ears]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10017-X Chapter 17 - Development of the Ears and Eyes]
|}

:'''Links:''' [[Embryology Textbooks]]

==Objectives==
* Understanding of sensory placode development
* Understanding of inner, middle and external ear origins
* Understanding of timecourse of auditory development
* Understanding of abnormalities of auditory development
* Brief understanding of other sensory development

{|
| [[File:Podcast_icon.jpg|link=ANAT2341_Embryology_2011_Lecture_Recordings]]
| '''Lectopia Lecture Audio'''

[[Media:Sensory Lecture 2011.mp3|Sensory Lecture 2011 Audio]]
This was the audio recording I prepared, not the iLecture.
|}

==Development Timing==
[[File:Stage14compare23.jpg|thumb|Comparison of size at stage 14 to 23]]
* '''Week 3''' - otic placode, otic vesicle
* '''Week 5''' - cochlear part of otic vesicle elongates (humans 2.5 turns)
* '''Week 9''' - Mesenchyme surrounding membranous labryinth (otic capsule) chondrifies
* '''Week 12-16''' - Capsule adjacent to membranous labryinth undegoes vacuolization to form a cavity (perilymphatic space) around membranous labrynth and fills with perilymph
* '''Week 16-24''' - Centres of ossification appear in remaining cartilage of otic capsule form petrous portion of temporal bone. Continues to ossify to form mastoid process of temporal bone.
* '''3rd Trimester''' - Vibration acoustically of maternal abdominal wall induces startle response in fetus.

==Embryonic Origin Overview==
[[File:Adult hearing embryonic origins.jpg|thumb|300px|Adult hearing embryonic origins]]
'''External Ear'''

* Auricle - Pharyngeal Arches 1 and 2 (ectoderm, mesoderm)
* External Auditory Meatus - Pharyngeal Arch 1 groove or cleft (ectoderm)
* Tympanic Membrane - Pharyngeal Arch 1 membrane (ectoderm, mesoderm, endoderm)

'''Middle Ear'''

* Middle Ear Ossicles
** Malleus and incus - Pharyngeal Arch 1 cartilage Neural crest (ectoderm)
** Stapes - Pharyngeal Arch 2 cartilage Neural crest (ectoderm)
* Middle Ear Muscles
** Tensor tympani - Pharyngeal Arch 1 (mesoderm)
** Stapedius - Pharyngeal Arch 2 (mesoderm)
* Middle ear cavity - Pharyngeal Arch 1 pouch (endoderm)

'''Inner Ear'''

* Inner Ear Labyrinth
** Cochlea - Otic vesicle - Otic placode (ectoderm)
** Semicircular canals - Otic vesicle - Otic placode (ectoderm)
** Saccule and utricle - Otic vesicle - Otic placode (ectoderm)
* Cranial Nerve VIII
** Auditory component - Otic vesicle and neural crest (ectoderm)
** Vestibular component - Otic vesicle and neural crest (ectoderm)

== Sensory Placodes ==
[[File:Stage11_sem20a.jpg|thumb|Otic placodes ([[Carnegie_stage_11|Stage 11]] dorsal view)]]
[[File:Stage14 sem2b-limb.jpg|thumb|Stage 14 sensory placodes]]
* week 4 a series of thickened surface ectodermal patches form in pairs in the head region.
** Recent research suggests that all sensory placodes may arise from common panplacodal primordium origin around the neural plate, and then differentiate to eventually have different developmental fates. PMID 20801420

* sensory placodes will later contribute key components of each of our special senses (vision, hearing and smell).
* Other species have a number of additional placodes which form other sensory structures (fish, lateral line receptor).
* Note that their initial postion on the developing head is significantly different to their final position in the future sensory system.

===Otic Placode===

* stage 13/14 embryo (shown below) the otic placode has sunk from the surface ectoderm to form a hollow epithelial ball, the otocyst, which now lies beneath the surface surrounded by mesenchyme (mesoderm).
* The epithelia of this ball varies in thickness and has begun to distort, it will eventually form the inner ear membranous labyrinth.

===Lens Placode===

* lies on the surface, adjacent to the outpocketing of the nervous system (which will for the retina) and will form the lens.

===Nasal Placode===

* 2 components (medial and lateral) and will form the nose olefactory epithelium.

:'''Links:''' [[Placodes]]

==Inner Ear==
[[File:Stage13 otocyst.jpg|thumb|Stage 13 otocyst]]
[[File:Stage22 ear.jpg|thumb|Stage 22 ear]]

* The inner ear is derived from a pair of surface sensory placodes (otic placodes) in the head region.
* These placodes fold inwards forming a depression, then pinch off entirely from the surface forming a fluid-filled sac or vesicle (otic vesicle, otocyst).
* The vesicle sinks into the head mesenchyme some of which closely surrounds the otocyst forming the otic capsule.
* The otocyst finally lies close to the early developing hindbrain (rhombencephalon) and the developing vestibulo-cochlear-facial ganglion complex.

:'''Links:''' [[Hearing - Inner Ear Development|Inner Ear]] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.894 Neuroscience - The Inner Ear]
==Middle Ear==
[[File:Pharyngeal arch cartilages.jpg|thumb|Pharyngeal arch cartilages]]
* The middle ear ossicles (bones) are derived from 1st and 2nd arch mesenchyme.
* The space in which these bones sit is derived from the 1st pharyngeal pouch.
** remains connected to the oral cavity by the auditory tube.

:'''Links:''' [[Hearing - Middle Ear Development|Middle Ear]] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.893 Neuroscience - The Middle Ear]
==Outer Ear==
[[File:External ear stages-14-23-adult.jpg|thumb|External ear stages 14-23 and adult (not to scale)]]
* The external ear is derived from 6 surface hillocks, 3 on each of pharyngeal arch 1 and 2.
* The external auditory meatus is derived from the 1st pharyngeal cleft.
* The newborn external ear structure and position is an easily accessible diagnostic tool for potential abnormalities or further clinical screening.

===Pinna- Auricle===
[[File:Streeter1922-plate01.jpg|thumb|arch 1 and 2 hillocks]]
* develops from six aural hillocks
* 3 on first arch
* 3 on second arch
* originally on neck, moves cranially during mandible development

{| class="prettytable"
| Pharyngeal Arch
| Hillock
| Auricle Component

|-
| Arch 1
| 1
| tragus

|-
|
| 2
| helix

|-
|
| 3
| cymba concha

|-
| Arch 2
| 4
| concha

|-
|
| 5
| antihelix

|-
|
| 6
| antitragus

|}

* Outer- external auditory meatus

* derived from first pharyngeal cleft
* ectodermal diverticulum
* week 5 - extends inwards to pharynx
* until week 18 has ectodermal plug - plug forms stratified squamous epithelia of canal and outer eardrum

'''Timeline'''
{|
|
* Embryonic Period - Ectodermal cells proliferate and fill the entire lumen forming a meatal plug
* 10 weeks - Meatal plug extends in a disc-like fashion. In the horizontal plane the meatus is boot-shaped with a narrow neck and the sole of the meatal plug spreading widely to form the future tympanic membrane medially. Proximal portion of the neck starts to be resorbed.
* 13 weeks - Disc-like plug innermost surface in contact with the primordial malleus, contributes to the formation of the tympanic membrane.
* 16.5 week - Meatus is fully patent throughout its length, lumen is still narrow and curved.
* 18 week - Meatus is already fully expanded to its complete form.

(EAM data - Nishimura, 1992 PMID 1441991)
| [[File:Gray0908.jpg|300px]]

outer ear and external auditory meatus
|}
'''Links:''' [[Hearing - Outer Ear Development|Outer Ear]] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.891 Neuroscience - The External Ear]

== Middle ==

===tympanic cavity===

* derived from first pharyngeal pouch
* extends as tubotympanic recess - during week 5 recess contacts outer ear canal
* mesoderm between 2 canals forms tympanic membrane
* expands to form tympanic recess
* stalk of recess forms auditory tube(eustachian tube, pharyngotympanic tube)

===Ossicles===
[[File:Pharyngeal arch cartilages.jpg|thumb|Pharyngeal arch cartilages]]
* develop from first and second pharyngeal arches
* tympanic cavity enlarges to incorporate
* coats with epithelia

* first arch mesoderm

* tensor tympani muscle
* malleus and incus

* second arch mesoderm

* stapedius muscle and stapes

Middle Ear Genes - gooscoid, RARs, Prx1, Otx2, Hoxa1, Hoxb1, endothelian related molecules

==Inner==
[[File:Stage11_sem20a.jpg|thumb|Otic placodes ([[Carnegie_stage_11|Stage 11]] dorsal view)]]
===Otocyst===
[[File:Stage12 sem1.jpg|thumb|Carnegie Stage 12 otic placode]]
[[File:Stage13_sem2c.jpg|thumb|Carnegie Stage 13 otic vesicle]]
<gallery>
Image:Gray0898.jpg
Image:Gray0899.jpg
Image:Gray0902.jpg
File:Stage_22_image_218.jpg|Week 8 cochlea
Image:Gray0903.jpg
Image:Gray0924.jpg
Image:Gray0928.jpg
Image:Gray0931.jpg
</gallery>
* week 3 otic placode forms on surface ectoderm
* otic placode sinks into mesoderm
* forms otocyst (otic vesicle)
* branches form and generate endolymphatic duct and sac
* forms vestibular (dorsal) and cochlear (ventral) regions
* differentiation of otic vesicle to membranous labyrinth

===Vestibular Sac ===

* generates 3 expansions - form semicircular ducts
* remainder forms utricle
* epithelia lining generates - hair cells, ampullary cristae, utricular macula
* Vestibular - Otoconia, otoconin- inner ear biominerals

===Cochlear sac===
{|
|
* generates coiled cochlear duct (humans 2 1/2 turns)
* remainder forms saccule
* epithelia lining generates
* hair cells
* structures of organ of corti
* saccular macula
| [[File:Stage_22_image_218.jpg|400px]]
|}

[[File:Inner ear haircells.jpg|thumb|Inner ear hair cells]]

===Bony Labyrinth===

* formed from chrondified mesoderm
* Periotic Capsule
* mesenchyme within capsule degenerates to form space filled with perilymph

===Vestibulocochlear Nerve===

* forms beside otocyst
* from wall of otocyst and neural crest cells
* bipolar neurons
* vestibular neurons
** outer end of internal acoustic meatus
** innervate hair cells in membranous labyrinth
** axons project to brain stem and synapse in vestibular nucleus
* cochlear neurons
** cell bodies lie in modiolus
** central pillar of cochlear
** innervate hair cells of spiral organ
** axons project to cochlear nucleus

Inner Ear Genes

* hindbrain segmentation occurs at same time placode arises
* otocyst adjacent to rhombomere 5
* may influence development
* Hoxa1, kreisler, Fgf3
* genes regulating neural crest cells (neural genes)
* Pax2 Ko affects cochlear and spiral ganglion, but not vestibular apparatus
* nerogenin 1 affects both ganglia

===Semicircular canal ===

* Otx1- cochlear and vestibular normal

* Hmx3, Prx1, Prx2

Sensory Organs

* thyroid hormone receptor beta
* Zebrafish-mindbomb mutant has excess hair cells but not supporting cells, Notch-Delta signaling

* Gene Expression-inner ear

* Brn-3c and Hair cell development
* Supporting Cells- p27kip
* Thyroid Hormone
* Ganglion neurons require growth factors
* vestibular neurons- BDNF, NT3
** survival not development

==Postnatal Changes==
[[Image:Eustacian tube angle.jpg|thumb|Eustacian tube angle changes]]
Newborn to adult Eustachian (auditory, otopharyngeal or pharyngotympanic) tube.
* Connects middle ear cavity to nasopharynx portion of pharynx

===Functions===
* Ventilation - pressure equalization in the middle ear
* Clearance - allow fluid drainage from the middle ear Tube is normally closed and opened by muscles

At birth
* shorter (17-18 mm), narrower and runs almost horizontal Tube is opened by a single muscle, tensor palati muscle

Adult
* longer (twice as long), wider and runs at approximately 45 degrees to the horizontal. Tube is opened by two separate muscles, tensor palati and levator palati

==Vision==

===Timeline===

* '''Weeks 3-4''' - Eye Fields-Optic Vesicle
* '''Weeks 5-6''' - Optic Cup, Lens Vesicle, Choroid Fissure, Hyaloid Artery
* '''Weeks 7-8''' - Cornea, Anterior Chamber, Pupillary Membrane, Lens, Retina
* '''Weeks 9-15''' - Iris, Ciliary Body
* '''Weeks 8-10''' - Eyelids

===Stage 13 (week 5)===

{|
| [[File:Stage 13 image 057.jpg|120px]]
| [[File:Stage 13 image 058.jpg|120px]]
| [[File:Stage 13 image 059.jpg|120px]]
| [[File:Stage 13 image 060.jpg|120px]]
| [[File:Stage 13 image 061.jpg|120px]]
| [[File:Stage 13 image 062.jpg|120px]]
| [[File:Stage 13 image 063.jpg|120px]]
|-
| [[:File:Stage 13 image 057.jpg|B1L]]
| [[:File:Stage 13 image 058.jpg|B2L]]
| [[:File:Stage 13 image 059.jpg|B3L]]
| [[:File:Stage 13 image 060.jpg|B4L]]
| [[:File:Stage 13 image 061.jpg|B5L]]
| [[:File:Stage 13 image 062.jpg|B6L]]
| [[:File:Stage 13 image 063.jpg|B7L]]
|}

===Lens===

Surface ectoderm -> lens placode (optic placode) -> lens pit -> lens vesicle -> lens fibres -> lens capsule and embryonic/fetal nucleus.

===Retina===

Neural plate ectoderm -> prosencephalon (forebrain) eye fields -> neural plate growth carries eye field region forward -> eye field invaginates forming optic grooves (sulci) -> diencephalon optic groove interacts with surface ectoderm (induces optic placode) -> optic stalk -> optic vesicle -> folds inward (optic cup) forming double layer -> inner neural retina, outer pigmented retina

Links: [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm Embryo Images - Eye Development]

===Neural Crest===

Eye connective tissue

==Abnormalities==
[[File:Hearing-vestibular sac abnormality.jpg|thumb|vestibular sac abnormality]]
* Inner - common cavity, severe cochlear hypoplasia
** Large vestibular aqueduct syndrome (LVAS) can be one of the common causes of hearing loss
* Middle - rare and can be part of first arch syndrome, Malleus, Incus and Stapes Fixation
** Cholesteatoma- Epithelium trapped within skull base in development, erosion of bones: temporal bone, middle ear, mastoid
* Outer - Several genetic effects and syndromes, Environmental Effects

Outer Ear Abnormalities
[[File:Microtia.jpg|thumb|Microtia]]
[[File:Preauricular sinus.jpg|thumb|Preauricular sinus]]
* Microtia - abnormally small external ear
* Preauricular sinus - occurs in 0.25% births, bilateral (hereditary) 25-50%, unilateral (mainly the left), duct runs inward can extend into the parotid gland, Postnatally sites for infection

Fetal Alcohol Syndrome
[[File:FASface.jpg|thumb|Fetal Alcohol Syndrome Face]]
* Postion- Lower or uneven height, "railroad track” appearance, curve at top part of outer ear is under-developed, folded over parallel to curve beneath

=== Congenital Deafness ===
'''Sensorineural''' - cochlear or central auditory pathway

* Hereditary
* recessive- severe
* dominant- mild
** can be associated with abnormal pigmentation (hair and irises)

* Acquired
** rubella (German measles), maternal infection during 2nd month of pregnancy, vaccination of young girls
** streptomycin
** antibiotic
** thalidomide

'''Conductive '''- disease of outer and middle ear
[[File:Eustacian_tube_angle.jpg|thumb|Eustacian tube angle]]

* produced by otitis media with effusion, is widespread in young children.
* temporary blockage of outer or middle ear

==Bionic Ear==
Cochlear Implant - Professor Graeme Clark (1960s, Australia) Array of electrodes implanted within cochlea, direct electrical stimulation to auditory nerve fibres

== Conductive Hearing Loss ==
* Conductive Hearing Loss Produces a Reversible Binaural Hearing Impairment David R. Moore, Jemma E. Hine, Ze Dong Jiang, Hiroaki Matsuda, Carl H. Parsons, and Andrew J. King J. Neurosci. 1999;19 8704-8711 [http://www.jneurosci.org/cgi/content/abstract/19/19/8704 http://www.jneurosci.org/cgi/content/abstract/19/19/8704]
** tested ferrets by lon-term plugging of ear canal
** Repeated testing during the 22 months after unplugging revealed a gradual return to normal levels of unmasking.
** Results show that a unilateral conductive hearing loss, in either infancy or adulthood, impairs binaural hearing both during and after the hearing loss.
** Show scant evidence for adaptation to the plug and demonstrate a recovery from the impairment that occurs over a period of several months after restoration of normal peripheral function.

== References ==
===Textbooks===
* '''Before We Are Born''' (5th ed.) Moore and Persaud Chapter 20: p460-479
* '''Essentials of Human Embryology''', Larson Chapter 12: p252-272

===Online Textbooks===
* '''Developmental Biology''' (6th ed.) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.figgrp.5455%20 Evolution of the mammalian middle ear bones from the reptilian jaw] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.figgrp.5460 Chick embryo rhombomere neural crest cells] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.table.3135 Some derivatives of the pharyngeal arches] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2871 Formation of the Neural Tube] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2884 Differentiation of the Neural Tube] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2894 Tissue Architecture of the Central Nervous System] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2908 Neuronal Types] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2937 Snapshot Summary: Central Nervous System and Epidermis]

* '''Neuroscience''' Purves, Dale; Augustine, George J.; Fitzpatrick, David; Katz, Lawrence C.; LaMantia, Anthony-Samuel; McNamara, James O.; Williams, S. Mark. Sunderland (MA): Sinauer Associates, Inc. ; c2001 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.879 The Auditory System] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.894 The Inner Ear] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.893 The Middle Ear] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.891 The External Ear] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.1447 Early Brain Development] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.1546 Construction of Neural Circuits] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.1640 Modification of Brain Circuits as a Result of Experience]

* '''Molecular Biology of the Cell''' (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002. [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.section.3963 Neural Development] | [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.figgrp.3966 The three phases of neural development]

* '''Clinical Methods''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.1949 63. Cranial Nerves IX and X: The Glossopharyngeal and Vagus Nerves] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3847 The Tongue] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3777 126. The Ear and Auditory System] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3627#3654 An Overview of the Head and Neck - Ears and Hearing] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3897 Audiometry]

* '''Health Services/Technology Assessment Text (HSTAT)''' Bethesda (MD): National Library of Medicine (US), 2003 Oct. [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=hstat1a.section.25014#25029 Developmental Disorders Associated with Failure to Thrive]

* '''Eurekah Bioscience Collection'''[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.chapter.53006 Cranial Neural Crest and Development of the Head Skeleton]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=hearing+development hearing development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=hearing+development hearing development]

==External Links==

{{External Links}}

* NIDCD - [http://www.nidcd.nih.gov/health/balance/balance_disorders.asp Balance Disorders]
* [http://www.med.unc.edu/embryo_images/ Embryo Images Online]
** '''Eye Development''' - [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm Eye Development Unit] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye001.htm Eye Fields-Optic Vesicle (Weeks 3-4)] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye009.htm Optic Cup, Lens Vesicle, Choroid Fissure, Hyaloid Artery (Weeks 5-6)] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye016.htm Cornea, Anterior Chamber, Pupillary Membrane, Lens, Retina (Weeks 7-8)] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye022.htm Iris, Cilliary Body (Weeks 9-15)] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye025.htm Eyelids (Weeks 8-10)]
** '''Ear Development''' - [http://www.med.unc.edu/embryo_images/unit-ear/ear_htms/eartoc.htm Ear Development Unit] | [http://www.med.unc.edu/embryo_images/unit-ear/ear_htms/ear001.htm Inner Ear | [http://www.med.unc.edu/embryo_images/unit-ear/ear_htms/ear012.htm Middle Ear] | [http://www.med.unc.edu/embryo_images/unit-ear/ear_htms/ear014.htm External Ear]

== Terms ==
* '''altricial animal''' - Term used to describe an animal born in a helpless state, with incomplete development of sensory systems at birth. For example rats and mice are born with incomplete development of visual and auditory systems.
* '''ampulla''' - Term used to describe an anatomical dilation of a tube or canal lumen. Anatomical description of the opening end of the uterine tube lying above the ovary and the enlarged initial segmeny of the semicircular canals of the inner ear vestibular system. (More? [ear6.htm Inner Ear] | [genitalXXuterus.htm Genital System - Female Uterus])
* '''aneurism''' - (Greek, ''aneurysma'' = a widening, aneurysm) A term used to describe an abnormal widening of a vessel or anatomical tubal structure.
* '''aquaeductus vestibuli '''- see vestibular aqueduct
* '''auditory neuropathy''' - (AN) abnormality of transmission of sound information to the brain.
* '''auditory tube '''- (eustachian tube) between the middle ear and oral cavity, has a bony (tympanic 1/3) and cartilaginous (pharyngeal 2/3) portion. The main role is equalization of pressure and fluid drainage in the middle ear.
* '''auricular hillock '''- see hillock
* '''atresia''' - narrowing, usually of an anatomical tube or cavity.
* '''autophagocytosis''' - (Greek, auto = self, phagy = eating, also called autophagy) a cell death mechanism that uses the cell's own lysosomes to self digest.
* '''border cells''' - columnar cells within the organ of Corti on the medial portion of the basilar membrane.
* '''canalis reuniens''' - (ductus reuniens, canaliculus reuniens, canalis reuniens, Hensen's canal, Hensen's duct, uniting canal, canalis reuniens of Hensen) short narrow canal connecting the cochlea duct to the saccule. (Victor Hensen, 1835-1924)
* '''cerumen''' - (ear wax) produced by glands in the skin of the outer portion of the ear canal.
* '''chondrified''' - the developmental differentiation of cartilage from mesenchye, an embryonic connective tissue.
* '''cristae ampullaris''' - located in the ampulla of the membranous semicircular canals a region with both supporting and hair cells. The hair cell cilia are embedded in the gelatinous cupula.
* '''claudius cells '''- (cells of Claudius) columnar cells with microvilli overlying the basilar membrane and extend from Hensen's cells to the spiral prominence. Barrier cells that lie external to the organ of corti in endolymph.
* '''cochlear sac '''- embryonic structure, which will form the coiled cochlear duct and contribute to the saccule.
* '''cochlear aqueduct''' - a bony channel containing the fibrous periotic duct. It connects the basal turn of the cochlea perilymphatic space with the subarachnoid space of the posterior cranial cavity.
* '''cochlin''' - major constituent of the inner ear extracellular matrix.
* '''collagen type II''' - major constituent of the inner ear extracellular matrix.
* '''conductive loss''' - term used to describe one of the two major classes of hearing loss involving external and middle ear abnormalities (other form is Sensorineural loss).
* '''connexins '''- channel proteins of the gap junctions that allow rapid communication between adjacent cells. The two connexins Cx26 and Cx30 are the major proteins of cochlear gap junctions.
* '''connexin 26''' - A strikingly high proportion (50%) of congenital bilateral nonsyndromic sensorineural deafness cases have been linked to mutations in the GJB2 coding for the connexin26
* '''cupular deposits''' - basophilic material on the cupulae of the semicircular ducts, an postnatal ageing phenomenon seen in some vestibular labyrinth.
* '''clinical weeks''' - taken from last menstrual period (LMP) and therefore approximately two weeks before fertilization occurs.
* Deiters' cells
* '''discoidin domain receptor 1''' - (DDR1) a tyrosine kinase receptor activated by native collagen, expressed in the basement membrane and with fibrillar collagens. Found in basal cells of the stria vascularis, type III fibrocytes, and cells lining the basilar membrane of the organ of Corti. {Meyer zum Gottesberge, 2008 #1877}
* ductus utriculosaccularis -
* '''endochondral ossification''' - the process of bone formation from a pre-existing cartilage template.
* endolymphatic fluid -
* '''endolymphatic sac''' - inner ear structure that has anatomically both an intraosseous and extraosseous component. Th e sac has functions regulating endolymph that are both secretory and absorptive. Also the site of endolymphatic sac tumors either sporadical occurring or associated with the autosomal-dominant von Hippel-Lindau (VHL) disease, due to a germ line mutation.
* '''embryological weeks''' - taken from the time of fertilization which typically occurs around the middle (day 14), or just after, of the typical 28 day menstrual cycle.
* '''Emx2''' - homeobox gene affecting middle ear and inner ear development.
* '''eustachian tube''' - (auditory tube) A cavity linking the pharynx to the middle ear, which develops from the first pharyngeal pouch. Named after Bartolomeo Eustachi (1500 - 1574) an Italian anatomist. Several functions including the equalization of pressure in the middle ear.
* '''external auditory meatus''' - (ear canal) develops from the first pharyngeal cleft.
* '''ear wax '''- see cerumen.
* '''espins''' - calcium-resistant actin-bundling proteins enriched in hair cell stereocilia and sensory cell microvilli and spiral ganglion neurons (SGNs)
* external auditory canal -
* '''fenestra ovalis''' - (oval window) separates the tympanic cavity from the vestibule of the osseous labyrinth.
* '''fenestra rotunda''' - (round window) separates the tympanic cavity from the scala tympani of the cochlea.
* '''fetus''' - (foetus) term used to describe human development after the 8th week (10th clinical week, LPM) and covers the developmental periods of second and third trimester.
* '''fibroblast growth factor 1''' - (Fgf-1) a growth factor released from cochlea sensory epithelium which stimulates spiral ganglion neurite branching.
* '''fibroblast growth factor 8''' - (Fgf-8) a growth factor released by inner hair cells which regulates pillar cell number, position and rate of development.
* '''fibroblast growth factor receptor 3''' - (Fgfr-3) a tyrosine kinase receptor with a role in the commitment, differentiation and position of pillar cells in the organ of corti
* '''fundamental frequency''' - (natural frequency) the lowest frequency in a harmonic series, for the female voice this is about 225 Hz.
* '''helicotrema''' - term used to describe the cochlear apex.
* Hes - (hairy and enhancer of split) family of factors, which has been shown to be a general negative regulator of neurogenesis (Zheng, 2000).
* '''hillock''' - a small hill, used to describe the six surface elevations on pharyngeal arch one and two.
* Hindbrain - Invaginate -
* '''Incus''' - (anvil) auditory ossicle
* inner phalangeal cells
* '''inner pillar cells''' - organ of Corti cells arranged in rows and form a boundary between the single row of inner hair cells and three rows of outer hair cells. These cells have surface-associated microtubule bundles.
* inner sulcus - area of the cochlear duct
* interdental region -
* '''internal auditory meatus''' - (internal acoustic meatus, IAM) Anatomical canal in which CN VII and CN VIII ganglia reside and pass through to the brainstem. This bony canal lies between the posterior surface of the petrous pyramid and the bony labyrinth within the dense petrous bone. Also associated clinically with the site where acoustic neuromas may occur.
* '''Kolliker's organ''' - (Kollicker's organ, greater epithelial ridge) Developing cochlear structure consisting of columnar-shaped supporting cells filling the inner sulcus and lying directly under the tectorial membrane. This transient organ regresses and generates the space of the inner sulcus. Rudolph Albert von Kolliker (1817-1905)??
* lateral semicircular duct -
* Limbus -
* '''LMP''' - acronym for last menstrual period, used to clinically measure gestation.
* '''malleus''' - (hammer) auditory ossicle
* '''mastoid process''' - of temporal bone
* '''Math1''' - homolog of the Drosophila proneural gene atonal, necessary and sufficient for the production of hair cells in the mouse inner ear. {Chen, 2002 #1932}Negatively regulated by Hes1 and Hes5
* '''meatal plug''' - temporary blockage of the external auditory meatus which forms at the end of the embryonic period and remains present until the seventh month.
* '''meatus''' - anatomical opening, cavity or space (external acoustic meatus,internal auditory meatus)
* '''Meckel's cartilage''' - first pharyngeal ach cartilage, located within the mandibular prominence. This cartilage first appears at stage 16, stage 20 the beginning of membranous ossification. Named after Johann Friedrich Meckel, (1781 - 1833) a German anatomist. (http://www.whonamedit.com/doctor.cfm/1840.html)
* membranous labyrinth - Mesenchyme - Mesoderm - Microtia - Modiolus -
* '''mucopolysaccharidosis''' - (MPS IIIB, Sanfilippo Syndrome type B) abnormality caused by a deficiency in the lysosomal enzyme N-acetyl-glucosaminidase (Naglu). Children with MPS IIIB develop abnormal hearing, and mental functioning culminating in early death.
* '''netrin-1''' - secreted growth factor, expressed in the organ of Corti and spiral ganglion cells, role in process outgrowth.
* neural tube -
* '''olivocochlear''' - brainstem cholinergic and GABAergic efferent system that innervates sensory cells and sensory neurons of the inner ear.
* organ of Corti - organ of Corti protein II - (OCP-II) cytosolic protein or transcription factor?
* '''otolithic membrane''' - extracellular matrix that cover the sensory epithelia of the inner ear.
* '''ossicle''' - (small bone) the individual bone of the three middle ear bones (auditory ossicles), which reduce vibrational amplitude but increase force to drive fluid-filled inner ear.
* ossify - the process of bone formation.
* otic capsule -
* otic cup
* otic placode -
* otic vesicle -
* '''otoconin''' - inner ear biominerals required for vestibular apparatus function.
* '''otogelin''' - (Otog) an inner ear specific glycoprotein expressed in cochlea cells at different developmental times.
* '''otolithic membrane''' - a membrane within the utricle and saccule containing embedded hair cell cilia and small crystalline bodies of calcium carbonate (otoliths). Functions to detect head motion.
* '''otoliths''' - small crystalline bodies of calcium carbonate found within the otolitic membrane of the utricle and saccule.
* '''ototoxic''' - compound or drug causing temporary or permanent hearing loss.
* '''outer hair cells''' - (OHCs) three rows of hair cells that function to increase basilar membrane motion through a local mechanical feedback process within the cochlea, the "cochlear amplifier".
* '''outer pillar cells''' - arranged in rows and form a boundary between the single row of inner hair cells and three rows of outer hair cells.
* '''paratubal musculature''' - muscles lying beside the auditory (Eustachian) tube. The tensor veli, palatini (TVP) and tensor tympani muscles.
* perilymph - perilymphatic space - Periotic Capsule - petrous portion - of temporal bone
* '''pejvakin gene''' - in humans, two missense mutations in this gene cause nonsyndromic recessive deafness (DFNB59) by affecting the function of auditory neurons.
* pharyngeal archpharyngeal pouchpharyngeal membranePharynx
* '''pillar cells''' - (PC) form an inner and outer row of support cells that form a boundary between inner and outer hair cells.
* Placode
* '''preyer reflex''' - ear flick in mouse in response to sound.
* presbyacusis
* '''prestin''' - a motor protein structurally similar to the anion transporter family expressed in cochlear outer hair cells.
* '''preauricular tag''' - skin tags located in front of the external ear opening, are common in neonates and in most cases are normal, though in some cases are indicative of other associated abnormalities.
* primordium-
* '''protocadherin 15''' - (Pcdh15) required for initial formation of stereocilia bundles and changes in the actin meshwork within hair cells. The Ames waltzer (av) mouse mutant has both auditory and vestibular abnormalities from a mutation in this gene.
* '''Reichert's cartilage''' - pharyngeal ach 2 cartilage, named after Karl Bogislaus Reichert (1811 - 1883) a German anatomist.
* '''Reissner's membrane''' - (vestibular membrane, vestibular wall) is a membrane located inside the cochlea separating the scala media from scala vestibuli. Named after Ernst Reissner (1824-1878) a German anatomist. ‚ÄúIt primarily functions as a diffusion barrier, allowing nutrients to travel from the perilymph to the endolymph of the membranous labyrinth.
* rhombomere -
* Saccular macula -
* Saccule - (Latin, sacculus = a small pouch)
* sacculocollic reflex -
* scala tympani - one of the three Cochlea cavities, it is filled with perilymph.
* '''Scarpa's ganglion''' - (vestibular ganglion) primary afferent vestibular neuron ganglion of the vestibular nerve. Located within the internal auditory meatus.
* '''semicircular canals''' - series of fluid-filled loops of the inner ear required for balance and sensing acceleration.
* sensorineural - term used to describe one of the two major classes of hearing loss involving the central pathway from the cochlear (other form is conductive loss).
* '''space of Nuel''' - within the cochlea, an organ of Corti space between the outer pillar cells and the phalangeal and hair cells. Named after Jean-Pierre Nuel (1847-1920) a Belgian ophthalmologist.
* '''spiral ganglion neurons''' - (SGN) innervate the inner (Type I) and outer (Type II) hair cells of the cochlea.
* '''stapedius muscle''' - (innervated by CN VII tympanic branch) one of the two muscles in the middle ear, contraction of this muscle pulls the stapes and dampens auditory ossicle movement.
* '''stapes''' - (stirrup) a middle ear auditory ossicle (bone).stapes footplate - startle response -
* '''stereocilia''' -finger-like projections from the apical surface of sensory hair cells forming the hair bundle in the cochlea. Formed by tightly cross-linked parallel actin filaments in a paracrystalline array with cell surface specializations (tip links, horizontal top connectors, and tectorial membrane attachment crowns).
* '''stratified squamous epithelia''' - classification of epithelium which transiently forms a plug in external ear canal to the outer eardrum.
* '''stria vascularis''' - forms the outer wall of the cochlear duct of the mammalian cochlea is composed primarily of three types of cells. Marginal cells line the lumen of the cochlear duct and are of epithelial origin. Basal cells also form a continuous layer and they may be mesodermal or derived from the neural crest. Intermediate cells are melanocyte-like cells, presumably derived from the neural crest, and are scattered between the marginal and basal cell layers. The stria forms endolymph and also contains a rich supply of blood vessels.
* sulcus -
* '''synostotically''' - anatomically normally separate skeletal bones fused together.
* '''tectorial membrane''' - extracellular matrix that cover the sensory epithelial hair cells of the organ of corti within the cochlea.
* '''alpha-tectorin and beta'''- (TECTA, TECTB) major non-collagenous protein component of the tectorial membrane forming a striated-sheet matrix. Synthesized as glycosylphosphatidylinositol-linked, membrane bound precursors.
* temporal bone -
* '''tensor tympani '''- (innervated by CN V mandibular nerve) one of the two muscles in the middle ear, contraction of this muscle pulls the malleus and tenses the tympanic membrane, dampening auditory ossicle movement. The muscle arises from auditory tube (cartilaginous portion) and is inserted into the malleus (manubrium near the root).
* teratogens - trilaminar embryo -
* '''tonotopy''' - term describing the mapping along the tectorial membrane within the cochlea of the different sound frequencies.
* tympanic cavity - tympanic membrane -Utricle -Vacuolization - Vesicle - vestibular apparatus - vestibular evoked myogenic potential (VEMP) test
* '''vestibular ganglion''' - (Scarpa's ganglion) primary afferent vestibular neuron ganglion of the vestibular nerve. Located within the internal auditory meatus.
* '''vestibular membrane''' - (Reissner's) extends from the spiral lamina to the outer wall and divides the cochlea into an upper scala vestibuli, a lower scala tympani.
* '''Vestibulocochlear Nerve''' - Cranial Nerve VIII
* '''Whirlin''' - A PDZ scaffold protein expressed in hair cells at the stereocilia tips, essential for the stereocilia elongation process. The DFNB31 gene mutations cause hearing loss in human and mouse. This protein can interact with membrane-associated guanylate kinase (MAGUK) protein, erythrocyte protein p55 (p55).
* '''Wnt7a''' - signaling through the Wnt pathway regulates the development of hair cell unidirectional stereociliary bundle orientation.

[[Category:Senses]] [[Category:Hearing]]

----

{{2012ANAT2341}}

Lecture - Neural Development

2013-10-10T23:16:20Z

Z3283213:

==Introduction==
[[File:Stage_22_image_217.jpg|thumb|300px|Cerebrum development human embryo (week 8, Stage 22)]]
'''Lecture Date: 2013-09-10 Lecture Time: 12:00 Venue: Wallace Wurth LG03; Speaker: Professor Ken Ashwell'''

'''The Powerpoint file used to present this lecture is available as a pdf document [[Media:LateDevCNS.pdf‎‎| HERE]]'''

'''A recording of the lecture will be available on Lectopia
[https://secured.learningandteaching.unsw.edu.au/lectopia/lectopiaLogin/default.cfm?ut=153 - Lectopia Login page]'''

{|

Lecture Date: 2013-10-15 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Ken Ashwell

|}

The information on this current page is provided only as background.

{{Neural Links}}

{{Neural Links 2}}

==Early Brain Structure==

===Primary Vesicles===
[[Image:CNS primary vesicles.jpg]]

* rostral neural tube forms 3 primary brain vesicles (week 4)
* 3 primary vesicles: '''prosencephalon''' (forebrain), '''mesencephalon''' (midbrain), '''rhombencephalon''' (hindbrain)

===Secondary Vesicles===
[[Image:CNS secondary vesicles.jpg]]

From the 3 primary vesicles developing to form 5 [[S#secondary vesicle|secondary vesicles]]
* prosencephalon- '''telencephalon''' (endbrain, forms cerebral hemispheres), '''diencephalon''' (betweenbrain, forms optic outgrowth)
* '''mesencephalon'''
* rhombencephalon- '''metencephalon''' (behindbrain), '''myelencephalon''' (medullabrain)

==Neural Layers==
===Brain===
{|
| [[File:Stage_22_image_150.jpg|400px]]
| [[File:Stage_22_image_151.jpg|400px]]
|-
| Human Embryo developing head cross section (Week 8, [[Carnegie stage 22|Stage 22]])
| Detail of developing cortex (shown in blue box)
|}

===Spinal Cord===
{|
| [[File:Stage_13_image_057.jpg|400px]]
| [[File:Stage 22 image 176.jpg|400px]]
|-
| Stage 13
| Stage 22
|}

==Fetal Neural==
[[File:Neural-development.jpg|600px]]

Timeline of events in Human Neural Development

[[File:Brain_ventricles_and_ganglia_development_03.jpg|500px]]

[[File:Brain_fissure_development_02.jpg|500px]]

{|
| [[File:Gray0654.jpg|250px]]
| [[File:Gray0655.jpg|250px]]
| [[File:Gray0658.jpg|250px]]
|-
| Human brain at three months (median sagittal section)
| Human brain at four months (inferior surface)
| Human brain at five months (outer surface)
|}
During the fetal period there is ongoing growth in size, weight and surface area of the brain and spinal cord. Microscopically there is ongoing: cell migration, extension of processes, cell death and glial cell development.

Cortical maturation (sulcation and gyration) and vascularization of the lateral surface of the brain starts with the insular cortex (insula, insulary cortex or insular lobe) region during the fetal period. This cerebral cortex region in the adult brain lies deep within the lateral sulcus between the temporal lobe and the parietal lobe.

* '''sulcation''' - The process of brain growth in the second to third trimester which forms sulci, grooves or folds visible on fetal brain surface as gyri grow (gyration). Abnormalities of these processes can lead to a smooth brain (lissencephaly).
* '''gyration''' - The development of surface folds on the brain (singular, gyrus)

Insular Gyral and Sulcal Development

* 13-17 gestational weeks - appearance of the first sulcus
* 18-19 gestational weeks - development of the periinsular sulci
* 20-22 gestational weeks - central sulci and opercularization of the insula
* 24-26 gestational weeks - covering of the posterior insula
* 27-28 gestational weeks - closure of the laeteral sulcus (Sylvian fissure or lateral fissure)

(Data from<ref><pubmed>17962979</pubmed></ref>)

* Between 29-41 weeks volumes of: total brain, cerebral gray matter, unmyelinated white matter, myelinated, and cerebrospinal fluid (from MRI)
** grey matter- mainly neuronal cell bodies; white matter- mainly neural processes and glia.
* total brain tissue volume increased linearly over this period at a rate of 22 ml/week.
* Total grey matter also showed a linear increase in relative intracranial volume of approximately 1.4% or 15 ml/week.
* The rapid increase in total grey matter is mainly due to a fourfold increase in cortical grey matter.
* Quantification of extracerebral and intraventricular CSF was found to change only minimally.

(Text - modified from <ref><pubmed>9485064</pubmed></ref>)

Neural development will continue after birth with substantial glial development, growth, death and reorganization occuring during the postnatally.

:'''Links:''' [[Neural System - Fetal]] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=neurosci&part=A1465&rendertype=figure&id=A1466 Neuroscience - Regional specification of the developing brain]

==Thyroid System and Neural Development==

[[File:Human thyroid system and neural development.jpg|800px]]

Timeline of human thyroid system and brain development from conception to birth.<ref><pubmed>12060827</pubmed></ref> (Estimation of neurogenesis adapted from Bayer et al.<ref><pubmed>8361683</pubmed></ref>)

:'''Links:''' [[Endocrine - Thyroid Development]]

==References==

<references/>

==Movies==

[[Computed Tomography]]

{| border='0px'
|-
| [[File:Mouse_CT_E11.5_movie-icon.jpg|120px|link=Quicktime Movie_-_CT_Mouse_E11.5]]
| [[File:Adult human brain movie icon.jpg|120px|link=Quicktime_Movie_-_Adult_Brain]]
|-
| [[Quicktime Movie_-_CT_Mouse_E11.5|Mouse E11.5 microCT scan]]
| [[Quicktime_Movie_-_Adult_Brain|Human Adult Brain]]
|-
|}

[[Magnetic Resonance Imaging]]

{| border='0px'
|+ '''Human Embryo'''
|-
| [[File:Brain_fissure_development_03.jpg|90px|link=Quicktime Movie - Neural Sylvian Fissure‎‎]]
|-
| [[Quicktime Movie - Neural Sylvian Fissure‎‎|Neural Sylvian Fissure]]
|-
|}

==Historic Embryology==

* [[Book_-_Contributions_to_Embryology_Carnegie_Institution_No.59|Contributions to Embryology Carnegie Institution No.59]] Relative Weight and Volume of the Component Parts of the Brain of the Human Embryo at Different Stages of Development. Jenkins, G.B. (1921). pp5-54.

===Images===
Bailey, F.R. and Miller, A.M. (1921). Text-Book of Embryology. New York: William Wood and Co.

[[Book_-_Text-Book_of_Embryology_17|The nervous system]]

<gallery>
File:Bailey358.jpg|Fig. 358 A two-neurone reflex arc in a Vertebrate
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</gallery>

Gray, Henry. Anatomy of the Human Body. Philadelphia: Lea & Febiger, 1918.

<gallery>
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</gallery>

----

{{2012ANAT2341}}

{{Glossary}}

{{Footer}}

Lecture - Sensory Development

2013-10-10T05:33:06Z

Z3283213:

==Introduction==
[[File:Stage14 sem2cl.jpg|thumb|Human embryo sensory placodes ([[Week 5]], [[Carnegie stage 14|stage 14]])]]
This lecture will introduce development of the special sensory structures associated with hearing, vision, smell and taste. Due to time limitations the lecture will focus on hearing development and if time is available vision and other senses will be introduced in general.

{|
| [[File:Hearing cartoon.jpg|160px|link=Sensory_-_Hearing_and_Balance_Development]]
| [[File:Stage_22_image_153.jpg|160px|link=Sensory_-_Vision_Development]]
| [[File:Stage_22_image_209.jpg|160px|link=Sensory_-_Smell_Development]]
| [[File:Tongue_-_taste_cartoon.jpg|160px|link=Sensory - Taste Development]]
|-
| <center>[[Sensory_-_Hearing_and_Balance_Development|Hearing Development]]</center>
| <center>[[Sensory_-_Vision_Development|Vision Development]]</center>
| <center>[[Sensory_-_Smell_Development|Smell Development]]</center>
| <center>[[Sensory - Taste Development|Taste Development]]</center>
|}

We use the sense of balance and hearing to position ourselves in space, sense our surrounding environment, and to communicate. Portions of the ear appear very early in development as specialized region (otic placode) on the embryo surface that sinks into the mesenchyme to form a vesicle (otic vesicle = otocyst) that form the inner ear.

This region connects centrally to the nervous system and peripherally through specialized bones to the external ear (auricle). This organisation develops different sources forming the 3 ear parts: inner ear (otic placode, otocyst), middle ear (1st pharyngeal pouch and 1st and 2nd arch mesenchyme), and outer ear (1st pharyngeal cleft and 6 surface hillocks).

This complex origin, organisation, and timecourse means that abnormal development of any one system can impact upon the development of hearing.

{|

Lecture Date: 2013-10-15 Lecture Time: 16:00 Venue: BioMed E Speaker: Prof. Ken Ashwell

|}

==Textbooks==
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Template:Senses Links}}

{{Template:Hearing Links}}

{{Template:Vision Links}}

{{Template:Taste Links}}

* [[2010_Lecture_17|2010 Lecture]] | [[2009 Lecture 17|2009 Lecture]] | [[BGD_Lecture_-_Face_and_Ear_Development|Medicine Lecture - Face and Ear Development]] | [[BGDB_Practical_-_Face_and_Ear_Development|Medicine Practical - Face and Ear Development]]

|}

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00018-7&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00018-7 Chapter 18 – Development of Eyes and Ears]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10017-X Chapter 17 - Development of the Ears and Eyes]
|}

:'''Links:''' [[Embryology Textbooks]]

==Objectives==
* Understanding of sensory placode development
* Understanding of inner, middle and external ear origins
* Understanding of timecourse of auditory development
* Understanding of abnormalities of auditory development
* Brief understanding of other sensory development

{|
| [[File:Podcast_icon.jpg|link=ANAT2341_Embryology_2011_Lecture_Recordings]]
| '''Lectopia Lecture Audio'''

[[Media:Sensory Lecture 2011.mp3|Sensory Lecture 2011 Audio]]
This was the audio recording I prepared, not the iLecture.
|}

==Development Timing==
[[File:Stage14compare23.jpg|thumb|Comparison of size at stage 14 to 23]]
* '''Week 3''' - otic placode, otic vesicle
* '''Week 5''' - cochlear part of otic vesicle elongates (humans 2.5 turns)
* '''Week 9''' - Mesenchyme surrounding membranous labryinth (otic capsule) chondrifies
* '''Week 12-16''' - Capsule adjacent to membranous labryinth undegoes vacuolization to form a cavity (perilymphatic space) around membranous labrynth and fills with perilymph
* '''Week 16-24''' - Centres of ossification appear in remaining cartilage of otic capsule form petrous portion of temporal bone. Continues to ossify to form mastoid process of temporal bone.
* '''3rd Trimester''' - Vibration acoustically of maternal abdominal wall induces startle response in fetus.

==Embryonic Origin Overview==
[[File:Adult hearing embryonic origins.jpg|thumb|300px|Adult hearing embryonic origins]]
'''External Ear'''

* Auricle - Pharyngeal Arches 1 and 2 (ectoderm, mesoderm)
* External Auditory Meatus - Pharyngeal Arch 1 groove or cleft (ectoderm)
* Tympanic Membrane - Pharyngeal Arch 1 membrane (ectoderm, mesoderm, endoderm)

'''Middle Ear'''

* Middle Ear Ossicles
** Malleus and incus - Pharyngeal Arch 1 cartilage Neural crest (ectoderm)
** Stapes - Pharyngeal Arch 2 cartilage Neural crest (ectoderm)
* Middle Ear Muscles
** Tensor tympani - Pharyngeal Arch 1 (mesoderm)
** Stapedius - Pharyngeal Arch 2 (mesoderm)
* Middle ear cavity - Pharyngeal Arch 1 pouch (endoderm)

'''Inner Ear'''

* Inner Ear Labyrinth
** Cochlea - Otic vesicle - Otic placode (ectoderm)
** Semicircular canals - Otic vesicle - Otic placode (ectoderm)
** Saccule and utricle - Otic vesicle - Otic placode (ectoderm)
* Cranial Nerve VIII
** Auditory component - Otic vesicle and neural crest (ectoderm)
** Vestibular component - Otic vesicle and neural crest (ectoderm)

== Sensory Placodes ==
[[File:Stage11_sem20a.jpg|thumb|Otic placodes ([[Carnegie_stage_11|Stage 11]] dorsal view)]]
[[File:Stage14 sem2b-limb.jpg|thumb|Stage 14 sensory placodes]]
* week 4 a series of thickened surface ectodermal patches form in pairs in the head region.
** Recent research suggests that all sensory placodes may arise from common panplacodal primordium origin around the neural plate, and then differentiate to eventually have different developmental fates. PMID 20801420

* sensory placodes will later contribute key components of each of our special senses (vision, hearing and smell).
* Other species have a number of additional placodes which form other sensory structures (fish, lateral line receptor).
* Note that their initial postion on the developing head is significantly different to their final position in the future sensory system.

===Otic Placode===

* stage 13/14 embryo (shown below) the otic placode has sunk from the surface ectoderm to form a hollow epithelial ball, the otocyst, which now lies beneath the surface surrounded by mesenchyme (mesoderm).
* The epithelia of this ball varies in thickness and has begun to distort, it will eventually form the inner ear membranous labyrinth.

===Lens Placode===

* lies on the surface, adjacent to the outpocketing of the nervous system (which will for the retina) and will form the lens.

===Nasal Placode===

* 2 components (medial and lateral) and will form the nose olefactory epithelium.

:'''Links:''' [[Placodes]]

==Inner Ear==
[[File:Stage13 otocyst.jpg|thumb|Stage 13 otocyst]]
[[File:Stage22 ear.jpg|thumb|Stage 22 ear]]

* The inner ear is derived from a pair of surface sensory placodes (otic placodes) in the head region.
* These placodes fold inwards forming a depression, then pinch off entirely from the surface forming a fluid-filled sac or vesicle (otic vesicle, otocyst).
* The vesicle sinks into the head mesenchyme some of which closely surrounds the otocyst forming the otic capsule.
* The otocyst finally lies close to the early developing hindbrain (rhombencephalon) and the developing vestibulo-cochlear-facial ganglion complex.

:'''Links:''' [[Hearing - Inner Ear Development|Inner Ear]] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.894 Neuroscience - The Inner Ear]
==Middle Ear==
[[File:Pharyngeal arch cartilages.jpg|thumb|Pharyngeal arch cartilages]]
* The middle ear ossicles (bones) are derived from 1st and 2nd arch mesenchyme.
* The space in which these bones sit is derived from the 1st pharyngeal pouch.
** remains connected to the oral cavity by the auditory tube.

:'''Links:''' [[Hearing - Middle Ear Development|Middle Ear]] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.893 Neuroscience - The Middle Ear]
==Outer Ear==
[[File:External ear stages-14-23-adult.jpg|thumb|External ear stages 14-23 and adult (not to scale)]]
* The external ear is derived from 6 surface hillocks, 3 on each of pharyngeal arch 1 and 2.
* The external auditory meatus is derived from the 1st pharyngeal cleft.
* The newborn external ear structure and position is an easily accessible diagnostic tool for potential abnormalities or further clinical screening.

===Pinna- Auricle===
[[File:Streeter1922-plate01.jpg|thumb|arch 1 and 2 hillocks]]
* develops from six aural hillocks
* 3 on first arch
* 3 on second arch
* originally on neck, moves cranially during mandible development

{| class="prettytable"
| Pharyngeal Arch
| Hillock
| Auricle Component

|-
| Arch 1
| 1
| tragus

|-
|
| 2
| helix

|-
|
| 3
| cymba concha

|-
| Arch 2
| 4
| concha

|-
|
| 5
| antihelix

|-
|
| 6
| antitragus

|}

* Outer- external auditory meatus

* derived from first pharyngeal cleft
* ectodermal diverticulum
* week 5 - extends inwards to pharynx
* until week 18 has ectodermal plug - plug forms stratified squamous epithelia of canal and outer eardrum

'''Timeline'''
{|
|
* Embryonic Period - Ectodermal cells proliferate and fill the entire lumen forming a meatal plug
* 10 weeks - Meatal plug extends in a disc-like fashion. In the horizontal plane the meatus is boot-shaped with a narrow neck and the sole of the meatal plug spreading widely to form the future tympanic membrane medially. Proximal portion of the neck starts to be resorbed.
* 13 weeks - Disc-like plug innermost surface in contact with the primordial malleus, contributes to the formation of the tympanic membrane.
* 16.5 week - Meatus is fully patent throughout its length, lumen is still narrow and curved.
* 18 week - Meatus is already fully expanded to its complete form.

(EAM data - Nishimura, 1992 PMID 1441991)
| [[File:Gray0908.jpg|300px]]

outer ear and external auditory meatus
|}
'''Links:''' [[Hearing - Outer Ear Development|Outer Ear]] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.891 Neuroscience - The External Ear]

== Middle ==

===tympanic cavity===

* derived from first pharyngeal pouch
* extends as tubotympanic recess - during week 5 recess contacts outer ear canal
* mesoderm between 2 canals forms tympanic membrane
* expands to form tympanic recess
* stalk of recess forms auditory tube(eustachian tube, pharyngotympanic tube)

===Ossicles===
[[File:Pharyngeal arch cartilages.jpg|thumb|Pharyngeal arch cartilages]]
* develop from first and second pharyngeal arches
* tympanic cavity enlarges to incorporate
* coats with epithelia

* first arch mesoderm

* tensor tympani muscle
* malleus and incus

* second arch mesoderm

* stapedius muscle and stapes

Middle Ear Genes - gooscoid, RARs, Prx1, Otx2, Hoxa1, Hoxb1, endothelian related molecules

==Inner==
[[File:Stage11_sem20a.jpg|thumb|Otic placodes ([[Carnegie_stage_11|Stage 11]] dorsal view)]]
===Otocyst===
[[File:Stage12 sem1.jpg|thumb|Carnegie Stage 12 otic placode]]
[[File:Stage13_sem2c.jpg|thumb|Carnegie Stage 13 otic vesicle]]
<gallery>
Image:Gray0898.jpg
Image:Gray0899.jpg
Image:Gray0902.jpg
File:Stage_22_image_218.jpg|Week 8 cochlea
Image:Gray0903.jpg
Image:Gray0924.jpg
Image:Gray0928.jpg
Image:Gray0931.jpg
</gallery>
* week 3 otic placode forms on surface ectoderm
* otic placode sinks into mesoderm
* forms otocyst (otic vesicle)
* branches form and generate endolymphatic duct and sac
* forms vestibular (dorsal) and cochlear (ventral) regions
* differentiation of otic vesicle to membranous labyrinth

===Vestibular Sac ===

* generates 3 expansions - form semicircular ducts
* remainder forms utricle
* epithelia lining generates - hair cells, ampullary cristae, utricular macula
* Vestibular - Otoconia, otoconin- inner ear biominerals

===Cochlear sac===
{|
|
* generates coiled cochlear duct (humans 2 1/2 turns)
* remainder forms saccule
* epithelia lining generates
* hair cells
* structures of organ of corti
* saccular macula
| [[File:Stage_22_image_218.jpg|400px]]
|}

[[File:Inner ear haircells.jpg|thumb|Inner ear hair cells]]

===Bony Labyrinth===

* formed from chrondified mesoderm
* Periotic Capsule
* mesenchyme within capsule degenerates to form space filled with perilymph

===Vestibulocochlear Nerve===

* forms beside otocyst
* from wall of otocyst and neural crest cells
* bipolar neurons
* vestibular neurons
** outer end of internal acoustic meatus
** innervate hair cells in membranous labyrinth
** axons project to brain stem and synapse in vestibular nucleus
* cochlear neurons
** cell bodies lie in modiolus
** central pillar of cochlear
** innervate hair cells of spiral organ
** axons project to cochlear nucleus

Inner Ear Genes

* hindbrain segmentation occurs at same time placode arises
* otocyst adjacent to rhombomere 5
* may influence development
* Hoxa1, kreisler, Fgf3
* genes regulating neural crest cells (neural genes)
* Pax2 Ko affects cochlear and spiral ganglion, but not vestibular apparatus
* nerogenin 1 affects both ganglia

===Semicircular canal ===

* Otx1- cochlear and vestibular normal

* Hmx3, Prx1, Prx2

Sensory Organs

* thyroid hormone receptor beta
* Zebrafish-mindbomb mutant has excess hair cells but not supporting cells, Notch-Delta signaling

* Gene Expression-inner ear

* Brn-3c and Hair cell development
* Supporting Cells- p27kip
* Thyroid Hormone
* Ganglion neurons require growth factors
* vestibular neurons- BDNF, NT3
** survival not development

==Postnatal Changes==
[[Image:Eustacian tube angle.jpg|thumb|Eustacian tube angle changes]]
Newborn to adult Eustachian (auditory, otopharyngeal or pharyngotympanic) tube.
* Connects middle ear cavity to nasopharynx portion of pharynx

===Functions===
* Ventilation - pressure equalization in the middle ear
* Clearance - allow fluid drainage from the middle ear Tube is normally closed and opened by muscles

At birth
* shorter (17-18 mm), narrower and runs almost horizontal Tube is opened by a single muscle, tensor palati muscle

Adult
* longer (twice as long), wider and runs at approximately 45 degrees to the horizontal. Tube is opened by two separate muscles, tensor palati and levator palati

==Vision==

===Timeline===

* '''Weeks 3-4''' - Eye Fields-Optic Vesicle
* '''Weeks 5-6''' - Optic Cup, Lens Vesicle, Choroid Fissure, Hyaloid Artery
* '''Weeks 7-8''' - Cornea, Anterior Chamber, Pupillary Membrane, Lens, Retina
* '''Weeks 9-15''' - Iris, Ciliary Body
* '''Weeks 8-10''' - Eyelids

===Stage 13 (week 5)===

{|
| [[File:Stage 13 image 057.jpg|120px]]
| [[File:Stage 13 image 058.jpg|120px]]
| [[File:Stage 13 image 059.jpg|120px]]
| [[File:Stage 13 image 060.jpg|120px]]
| [[File:Stage 13 image 061.jpg|120px]]
| [[File:Stage 13 image 062.jpg|120px]]
| [[File:Stage 13 image 063.jpg|120px]]
|-
| [[:File:Stage 13 image 057.jpg|B1L]]
| [[:File:Stage 13 image 058.jpg|B2L]]
| [[:File:Stage 13 image 059.jpg|B3L]]
| [[:File:Stage 13 image 060.jpg|B4L]]
| [[:File:Stage 13 image 061.jpg|B5L]]
| [[:File:Stage 13 image 062.jpg|B6L]]
| [[:File:Stage 13 image 063.jpg|B7L]]
|}

===Lens===

Surface ectoderm -> lens placode (optic placode) -> lens pit -> lens vesicle -> lens fibres -> lens capsule and embryonic/fetal nucleus.

===Retina===

Neural plate ectoderm -> prosencephalon (forebrain) eye fields -> neural plate growth carries eye field region forward -> eye field invaginates forming optic grooves (sulci) -> diencephalon optic groove interacts with surface ectoderm (induces optic placode) -> optic stalk -> optic vesicle -> folds inward (optic cup) forming double layer -> inner neural retina, outer pigmented retina

Links: [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm Embryo Images - Eye Development]

===Neural Crest===

Eye connective tissue

==Abnormalities==
[[File:Hearing-vestibular sac abnormality.jpg|thumb|vestibular sac abnormality]]
* Inner - common cavity, severe cochlear hypoplasia
** Large vestibular aqueduct syndrome (LVAS) can be one of the common causes of hearing loss
* Middle - rare and can be part of first arch syndrome, Malleus, Incus and Stapes Fixation
** Cholesteatoma- Epithelium trapped within skull base in development, erosion of bones: temporal bone, middle ear, mastoid
* Outer - Several genetic effects and syndromes, Environmental Effects

Outer Ear Abnormalities
[[File:Microtia.jpg|thumb|Microtia]]
[[File:Preauricular sinus.jpg|thumb|Preauricular sinus]]
* Microtia - abnormally small external ear
* Preauricular sinus - occurs in 0.25% births, bilateral (hereditary) 25-50%, unilateral (mainly the left), duct runs inward can extend into the parotid gland, Postnatally sites for infection

Fetal Alcohol Syndrome
[[File:FASface.jpg|thumb|Fetal Alcohol Syndrome Face]]
* Postion- Lower or uneven height, "railroad track” appearance, curve at top part of outer ear is under-developed, folded over parallel to curve beneath

=== Congenital Deafness ===
'''Sensorineural''' - cochlear or central auditory pathway

* Hereditary
* recessive- severe
* dominant- mild
** can be associated with abnormal pigmentation (hair and irises)

* Acquired
** rubella (German measles), maternal infection during 2nd month of pregnancy, vaccination of young girls
** streptomycin
** antibiotic
** thalidomide

'''Conductive '''- disease of outer and middle ear
[[File:Eustacian_tube_angle.jpg|thumb|Eustacian tube angle]]

* produced by otitis media with effusion, is widespread in young children.
* temporary blockage of outer or middle ear

==Bionic Ear==
Cochlear Implant - Professor Graeme Clark (1960s, Australia) Array of electrodes implanted within cochlea, direct electrical stimulation to auditory nerve fibres

== Conductive Hearing Loss ==
* Conductive Hearing Loss Produces a Reversible Binaural Hearing Impairment David R. Moore, Jemma E. Hine, Ze Dong Jiang, Hiroaki Matsuda, Carl H. Parsons, and Andrew J. King J. Neurosci. 1999;19 8704-8711 [http://www.jneurosci.org/cgi/content/abstract/19/19/8704 http://www.jneurosci.org/cgi/content/abstract/19/19/8704]
** tested ferrets by lon-term plugging of ear canal
** Repeated testing during the 22 months after unplugging revealed a gradual return to normal levels of unmasking.
** Results show that a unilateral conductive hearing loss, in either infancy or adulthood, impairs binaural hearing both during and after the hearing loss.
** Show scant evidence for adaptation to the plug and demonstrate a recovery from the impairment that occurs over a period of several months after restoration of normal peripheral function.

== References ==
===Textbooks===
* '''Before We Are Born''' (5th ed.) Moore and Persaud Chapter 20: p460-479
* '''Essentials of Human Embryology''', Larson Chapter 12: p252-272

===Online Textbooks===
* '''Developmental Biology''' (6th ed.) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.figgrp.5455%20 Evolution of the mammalian middle ear bones from the reptilian jaw] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.figgrp.5460 Chick embryo rhombomere neural crest cells] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.table.3135 Some derivatives of the pharyngeal arches] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2871 Formation of the Neural Tube] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2884 Differentiation of the Neural Tube] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2894 Tissue Architecture of the Central Nervous System] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2908 Neuronal Types] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2937 Snapshot Summary: Central Nervous System and Epidermis]

* '''Neuroscience''' Purves, Dale; Augustine, George J.; Fitzpatrick, David; Katz, Lawrence C.; LaMantia, Anthony-Samuel; McNamara, James O.; Williams, S. Mark. Sunderland (MA): Sinauer Associates, Inc. ; c2001 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.879 The Auditory System] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.894 The Inner Ear] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.893 The Middle Ear] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.891 The External Ear] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.1447 Early Brain Development] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.1546 Construction of Neural Circuits] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.1640 Modification of Brain Circuits as a Result of Experience]

* '''Molecular Biology of the Cell''' (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002. [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.section.3963 Neural Development] | [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.figgrp.3966 The three phases of neural development]

* '''Clinical Methods''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.1949 63. Cranial Nerves IX and X: The Glossopharyngeal and Vagus Nerves] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3847 The Tongue] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3777 126. The Ear and Auditory System] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3627#3654 An Overview of the Head and Neck - Ears and Hearing] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3897 Audiometry]

* '''Health Services/Technology Assessment Text (HSTAT)''' Bethesda (MD): National Library of Medicine (US), 2003 Oct. [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=hstat1a.section.25014#25029 Developmental Disorders Associated with Failure to Thrive]

* '''Eurekah Bioscience Collection'''[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.chapter.53006 Cranial Neural Crest and Development of the Head Skeleton]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=hearing+development hearing development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=hearing+development hearing development]

==External Links==

{{External Links}}

* NIDCD - [http://www.nidcd.nih.gov/health/balance/balance_disorders.asp Balance Disorders]
* [http://www.med.unc.edu/embryo_images/ Embryo Images Online]
** '''Eye Development''' - [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm Eye Development Unit] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye001.htm Eye Fields-Optic Vesicle (Weeks 3-4)] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye009.htm Optic Cup, Lens Vesicle, Choroid Fissure, Hyaloid Artery (Weeks 5-6)] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye016.htm Cornea, Anterior Chamber, Pupillary Membrane, Lens, Retina (Weeks 7-8)] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye022.htm Iris, Cilliary Body (Weeks 9-15)] | [http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eye025.htm Eyelids (Weeks 8-10)]
** '''Ear Development''' - [http://www.med.unc.edu/embryo_images/unit-ear/ear_htms/eartoc.htm Ear Development Unit] | [http://www.med.unc.edu/embryo_images/unit-ear/ear_htms/ear001.htm Inner Ear | [http://www.med.unc.edu/embryo_images/unit-ear/ear_htms/ear012.htm Middle Ear] | [http://www.med.unc.edu/embryo_images/unit-ear/ear_htms/ear014.htm External Ear]

== Terms ==
* '''altricial animal''' - Term used to describe an animal born in a helpless state, with incomplete development of sensory systems at birth. For example rats and mice are born with incomplete development of visual and auditory systems.
* '''ampulla''' - Term used to describe an anatomical dilation of a tube or canal lumen. Anatomical description of the opening end of the uterine tube lying above the ovary and the enlarged initial segmeny of the semicircular canals of the inner ear vestibular system. (More? [ear6.htm Inner Ear] | [genitalXXuterus.htm Genital System - Female Uterus])
* '''aneurism''' - (Greek, ''aneurysma'' = a widening, aneurysm) A term used to describe an abnormal widening of a vessel or anatomical tubal structure.
* '''aquaeductus vestibuli '''- see vestibular aqueduct
* '''auditory neuropathy''' - (AN) abnormality of transmission of sound information to the brain.
* '''auditory tube '''- (eustachian tube) between the middle ear and oral cavity, has a bony (tympanic 1/3) and cartilaginous (pharyngeal 2/3) portion. The main role is equalization of pressure and fluid drainage in the middle ear.
* '''auricular hillock '''- see hillock
* '''atresia''' - narrowing, usually of an anatomical tube or cavity.
* '''autophagocytosis''' - (Greek, auto = self, phagy = eating, also called autophagy) a cell death mechanism that uses the cell's own lysosomes to self digest.
* '''border cells''' - columnar cells within the organ of Corti on the medial portion of the basilar membrane.
* '''canalis reuniens''' - (ductus reuniens, canaliculus reuniens, canalis reuniens, Hensen's canal, Hensen's duct, uniting canal, canalis reuniens of Hensen) short narrow canal connecting the cochlea duct to the saccule. (Victor Hensen, 1835-1924)
* '''cerumen''' - (ear wax) produced by glands in the skin of the outer portion of the ear canal.
* '''chondrified''' - the developmental differentiation of cartilage from mesenchye, an embryonic connective tissue.
* '''cristae ampullaris''' - located in the ampulla of the membranous semicircular canals a region with both supporting and hair cells. The hair cell cilia are embedded in the gelatinous cupula.
* '''claudius cells '''- (cells of Claudius) columnar cells with microvilli overlying the basilar membrane and extend from Hensen's cells to the spiral prominence. Barrier cells that lie external to the organ of corti in endolymph.
* '''cochlear sac '''- embryonic structure, which will form the coiled cochlear duct and contribute to the saccule.
* '''cochlear aqueduct''' - a bony channel containing the fibrous periotic duct. It connects the basal turn of the cochlea perilymphatic space with the subarachnoid space of the posterior cranial cavity.
* '''cochlin''' - major constituent of the inner ear extracellular matrix.
* '''collagen type II''' - major constituent of the inner ear extracellular matrix.
* '''conductive loss''' - term used to describe one of the two major classes of hearing loss involving external and middle ear abnormalities (other form is Sensorineural loss).
* '''connexins '''- channel proteins of the gap junctions that allow rapid communication between adjacent cells. The two connexins Cx26 and Cx30 are the major proteins of cochlear gap junctions.
* '''connexin 26''' - A strikingly high proportion (50%) of congenital bilateral nonsyndromic sensorineural deafness cases have been linked to mutations in the GJB2 coding for the connexin26
* '''cupular deposits''' - basophilic material on the cupulae of the semicircular ducts, an postnatal ageing phenomenon seen in some vestibular labyrinth.
* '''clinical weeks''' - taken from last menstrual period (LMP) and therefore approximately two weeks before fertilization occurs.
* Deiters' cells
* '''discoidin domain receptor 1''' - (DDR1) a tyrosine kinase receptor activated by native collagen, expressed in the basement membrane and with fibrillar collagens. Found in basal cells of the stria vascularis, type III fibrocytes, and cells lining the basilar membrane of the organ of Corti. {Meyer zum Gottesberge, 2008 #1877}
* ductus utriculosaccularis -
* '''endochondral ossification''' - the process of bone formation from a pre-existing cartilage template.
* endolymphatic fluid -
* '''endolymphatic sac''' - inner ear structure that has anatomically both an intraosseous and extraosseous component. Th e sac has functions regulating endolymph that are both secretory and absorptive. Also the site of endolymphatic sac tumors either sporadical occurring or associated with the autosomal-dominant von Hippel-Lindau (VHL) disease, due to a germ line mutation.
* '''embryological weeks''' - taken from the time of fertilization which typically occurs around the middle (day 14), or just after, of the typical 28 day menstrual cycle.
* '''Emx2''' - homeobox gene affecting middle ear and inner ear development.
* '''eustachian tube''' - (auditory tube) A cavity linking the pharynx to the middle ear, which develops from the first pharyngeal pouch. Named after Bartolomeo Eustachi (1500 - 1574) an Italian anatomist. Several functions including the equalization of pressure in the middle ear.
* '''external auditory meatus''' - (ear canal) develops from the first pharyngeal cleft.
* '''ear wax '''- see cerumen.
* '''espins''' - calcium-resistant actin-bundling proteins enriched in hair cell stereocilia and sensory cell microvilli and spiral ganglion neurons (SGNs)
* external auditory canal -
* '''fenestra ovalis''' - (oval window) separates the tympanic cavity from the vestibule of the osseous labyrinth.
* '''fenestra rotunda''' - (round window) separates the tympanic cavity from the scala tympani of the cochlea.
* '''fetus''' - (foetus) term used to describe human development after the 8th week (10th clinical week, LPM) and covers the developmental periods of second and third trimester.
* '''fibroblast growth factor 1''' - (Fgf-1) a growth factor released from cochlea sensory epithelium which stimulates spiral ganglion neurite branching.
* '''fibroblast growth factor 8''' - (Fgf-8) a growth factor released by inner hair cells which regulates pillar cell number, position and rate of development.
* '''fibroblast growth factor receptor 3''' - (Fgfr-3) a tyrosine kinase receptor with a role in the commitment, differentiation and position of pillar cells in the organ of corti
* '''fundamental frequency''' - (natural frequency) the lowest frequency in a harmonic series, for the female voice this is about 225 Hz.
* '''helicotrema''' - term used to describe the cochlear apex.
* Hes - (hairy and enhancer of split) family of factors, which has been shown to be a general negative regulator of neurogenesis (Zheng, 2000).
* '''hillock''' - a small hill, used to describe the six surface elevations on pharyngeal arch one and two.
* Hindbrain - Invaginate -
* '''Incus''' - (anvil) auditory ossicle
* inner phalangeal cells
* '''inner pillar cells''' - organ of Corti cells arranged in rows and form a boundary between the single row of inner hair cells and three rows of outer hair cells. These cells have surface-associated microtubule bundles.
* inner sulcus - area of the cochlear duct
* interdental region -
* '''internal auditory meatus''' - (internal acoustic meatus, IAM) Anatomical canal in which CN VII and CN VIII ganglia reside and pass through to the brainstem. This bony canal lies between the posterior surface of the petrous pyramid and the bony labyrinth within the dense petrous bone. Also associated clinically with the site where acoustic neuromas may occur.
* '''Kolliker's organ''' - (Kollicker's organ, greater epithelial ridge) Developing cochlear structure consisting of columnar-shaped supporting cells filling the inner sulcus and lying directly under the tectorial membrane. This transient organ regresses and generates the space of the inner sulcus. Rudolph Albert von Kolliker (1817-1905)??
* lateral semicircular duct -
* Limbus -
* '''LMP''' - acronym for last menstrual period, used to clinically measure gestation.
* '''malleus''' - (hammer) auditory ossicle
* '''mastoid process''' - of temporal bone
* '''Math1''' - homolog of the Drosophila proneural gene atonal, necessary and sufficient for the production of hair cells in the mouse inner ear. {Chen, 2002 #1932}Negatively regulated by Hes1 and Hes5
* '''meatal plug''' - temporary blockage of the external auditory meatus which forms at the end of the embryonic period and remains present until the seventh month.
* '''meatus''' - anatomical opening, cavity or space (external acoustic meatus,internal auditory meatus)
* '''Meckel's cartilage''' - first pharyngeal ach cartilage, located within the mandibular prominence. This cartilage first appears at stage 16, stage 20 the beginning of membranous ossification. Named after Johann Friedrich Meckel, (1781 - 1833) a German anatomist. (http://www.whonamedit.com/doctor.cfm/1840.html)
* membranous labyrinth - Mesenchyme - Mesoderm - Microtia - Modiolus -
* '''mucopolysaccharidosis''' - (MPS IIIB, Sanfilippo Syndrome type B) abnormality caused by a deficiency in the lysosomal enzyme N-acetyl-glucosaminidase (Naglu). Children with MPS IIIB develop abnormal hearing, and mental functioning culminating in early death.
* '''netrin-1''' - secreted growth factor, expressed in the organ of Corti and spiral ganglion cells, role in process outgrowth.
* neural tube -
* '''olivocochlear''' - brainstem cholinergic and GABAergic efferent system that innervates sensory cells and sensory neurons of the inner ear.
* organ of Corti - organ of Corti protein II - (OCP-II) cytosolic protein or transcription factor?
* '''otolithic membrane''' - extracellular matrix that cover the sensory epithelia of the inner ear.
* '''ossicle''' - (small bone) the individual bone of the three middle ear bones (auditory ossicles), which reduce vibrational amplitude but increase force to drive fluid-filled inner ear.
* ossify - the process of bone formation.
* otic capsule -
* otic cup
* otic placode -
* otic vesicle -
* '''otoconin''' - inner ear biominerals required for vestibular apparatus function.
* '''otogelin''' - (Otog) an inner ear specific glycoprotein expressed in cochlea cells at different developmental times.
* '''otolithic membrane''' - a membrane within the utricle and saccule containing embedded hair cell cilia and small crystalline bodies of calcium carbonate (otoliths). Functions to detect head motion.
* '''otoliths''' - small crystalline bodies of calcium carbonate found within the otolitic membrane of the utricle and saccule.
* '''ototoxic''' - compound or drug causing temporary or permanent hearing loss.
* '''outer hair cells''' - (OHCs) three rows of hair cells that function to increase basilar membrane motion through a local mechanical feedback process within the cochlea, the "cochlear amplifier".
* '''outer pillar cells''' - arranged in rows and form a boundary between the single row of inner hair cells and three rows of outer hair cells.
* '''paratubal musculature''' - muscles lying beside the auditory (Eustachian) tube. The tensor veli, palatini (TVP) and tensor tympani muscles.
* perilymph - perilymphatic space - Periotic Capsule - petrous portion - of temporal bone
* '''pejvakin gene''' - in humans, two missense mutations in this gene cause nonsyndromic recessive deafness (DFNB59) by affecting the function of auditory neurons.
* pharyngeal archpharyngeal pouchpharyngeal membranePharynx
* '''pillar cells''' - (PC) form an inner and outer row of support cells that form a boundary between inner and outer hair cells.
* Placode
* '''preyer reflex''' - ear flick in mouse in response to sound.
* presbyacusis
* '''prestin''' - a motor protein structurally similar to the anion transporter family expressed in cochlear outer hair cells.
* '''preauricular tag''' - skin tags located in front of the external ear opening, are common in neonates and in most cases are normal, though in some cases are indicative of other associated abnormalities.
* primordium-
* '''protocadherin 15''' - (Pcdh15) required for initial formation of stereocilia bundles and changes in the actin meshwork within hair cells. The Ames waltzer (av) mouse mutant has both auditory and vestibular abnormalities from a mutation in this gene.
* '''Reichert's cartilage''' - pharyngeal ach 2 cartilage, named after Karl Bogislaus Reichert (1811 - 1883) a German anatomist.
* '''Reissner's membrane''' - (vestibular membrane, vestibular wall) is a membrane located inside the cochlea separating the scala media from scala vestibuli. Named after Ernst Reissner (1824-1878) a German anatomist. ‚ÄúIt primarily functions as a diffusion barrier, allowing nutrients to travel from the perilymph to the endolymph of the membranous labyrinth.
* rhombomere -
* Saccular macula -
* Saccule - (Latin, sacculus = a small pouch)
* sacculocollic reflex -
* scala tympani - one of the three Cochlea cavities, it is filled with perilymph.
* '''Scarpa's ganglion''' - (vestibular ganglion) primary afferent vestibular neuron ganglion of the vestibular nerve. Located within the internal auditory meatus.
* '''semicircular canals''' - series of fluid-filled loops of the inner ear required for balance and sensing acceleration.
* sensorineural - term used to describe one of the two major classes of hearing loss involving the central pathway from the cochlear (other form is conductive loss).
* '''space of Nuel''' - within the cochlea, an organ of Corti space between the outer pillar cells and the phalangeal and hair cells. Named after Jean-Pierre Nuel (1847-1920) a Belgian ophthalmologist.
* '''spiral ganglion neurons''' - (SGN) innervate the inner (Type I) and outer (Type II) hair cells of the cochlea.
* '''stapedius muscle''' - (innervated by CN VII tympanic branch) one of the two muscles in the middle ear, contraction of this muscle pulls the stapes and dampens auditory ossicle movement.
* '''stapes''' - (stirrup) a middle ear auditory ossicle (bone).stapes footplate - startle response -
* '''stereocilia''' -finger-like projections from the apical surface of sensory hair cells forming the hair bundle in the cochlea. Formed by tightly cross-linked parallel actin filaments in a paracrystalline array with cell surface specializations (tip links, horizontal top connectors, and tectorial membrane attachment crowns).
* '''stratified squamous epithelia''' - classification of epithelium which transiently forms a plug in external ear canal to the outer eardrum.
* '''stria vascularis''' - forms the outer wall of the cochlear duct of the mammalian cochlea is composed primarily of three types of cells. Marginal cells line the lumen of the cochlear duct and are of epithelial origin. Basal cells also form a continuous layer and they may be mesodermal or derived from the neural crest. Intermediate cells are melanocyte-like cells, presumably derived from the neural crest, and are scattered between the marginal and basal cell layers. The stria forms endolymph and also contains a rich supply of blood vessels.
* sulcus -
* '''synostotically''' - anatomically normally separate skeletal bones fused together.
* '''tectorial membrane''' - extracellular matrix that cover the sensory epithelial hair cells of the organ of corti within the cochlea.
* '''alpha-tectorin and beta'''- (TECTA, TECTB) major non-collagenous protein component of the tectorial membrane forming a striated-sheet matrix. Synthesized as glycosylphosphatidylinositol-linked, membrane bound precursors.
* temporal bone -
* '''tensor tympani '''- (innervated by CN V mandibular nerve) one of the two muscles in the middle ear, contraction of this muscle pulls the malleus and tenses the tympanic membrane, dampening auditory ossicle movement. The muscle arises from auditory tube (cartilaginous portion) and is inserted into the malleus (manubrium near the root).
* teratogens - trilaminar embryo -
* '''tonotopy''' - term describing the mapping along the tectorial membrane within the cochlea of the different sound frequencies.
* tympanic cavity - tympanic membrane -Utricle -Vacuolization - Vesicle - vestibular apparatus - vestibular evoked myogenic potential (VEMP) test
* '''vestibular ganglion''' - (Scarpa's ganglion) primary afferent vestibular neuron ganglion of the vestibular nerve. Located within the internal auditory meatus.
* '''vestibular membrane''' - (Reissner's) extends from the spiral lamina to the outer wall and divides the cochlea into an upper scala vestibuli, a lower scala tympani.
* '''Vestibulocochlear Nerve''' - Cranial Nerve VIII
* '''Whirlin''' - A PDZ scaffold protein expressed in hair cells at the stereocilia tips, essential for the stereocilia elongation process. The DFNB31 gene mutations cause hearing loss in human and mouse. This protein can interact with membrane-associated guanylate kinase (MAGUK) protein, erythrocyte protein p55 (p55).
* '''Wnt7a''' - signaling through the Wnt pathway regulates the development of hair cell unidirectional stereociliary bundle orientation.

[[Category:Senses]] [[Category:Hearing]]

----

{{2012ANAT2341}}

Lecture - Neural Development

2013-10-10T05:28:11Z

Z3283213:

==Introduction==
[[File:Stage_22_image_217.jpg|thumb|300px|Cerebrum development human embryo (week 8, Stage 22)]]
This will be a guest lecturer Prof. Ken Ashwell, who will provide his own lecture notes linked below.

:[[Media:2011 Lecture - Neural Development.pdf|Lecture Slides PDF]] (3.08 MB 48 Slides)

{|

Lecture Date: 2013-10-15 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Ken Ashwell

|}

The information on this current page is provided only as background.

{{Neural Links}}

{{Neural Links 2}}

==Early Brain Structure==

===Primary Vesicles===
[[Image:CNS primary vesicles.jpg]]

* rostral neural tube forms 3 primary brain vesicles (week 4)
* 3 primary vesicles: '''prosencephalon''' (forebrain), '''mesencephalon''' (midbrain), '''rhombencephalon''' (hindbrain)

===Secondary Vesicles===
[[Image:CNS secondary vesicles.jpg]]

From the 3 primary vesicles developing to form 5 [[S#secondary vesicle|secondary vesicles]]
* prosencephalon- '''telencephalon''' (endbrain, forms cerebral hemispheres), '''diencephalon''' (betweenbrain, forms optic outgrowth)
* '''mesencephalon'''
* rhombencephalon- '''metencephalon''' (behindbrain), '''myelencephalon''' (medullabrain)

==Neural Layers==
===Brain===
{|
| [[File:Stage_22_image_150.jpg|400px]]
| [[File:Stage_22_image_151.jpg|400px]]
|-
| Human Embryo developing head cross section (Week 8, [[Carnegie stage 22|Stage 22]])
| Detail of developing cortex (shown in blue box)
|}

===Spinal Cord===
{|
| [[File:Stage_13_image_057.jpg|400px]]
| [[File:Stage 22 image 176.jpg|400px]]
|-
| Stage 13
| Stage 22
|}

==Fetal Neural==
[[File:Neural-development.jpg|600px]]

Timeline of events in Human Neural Development

[[File:Brain_ventricles_and_ganglia_development_03.jpg|500px]]

[[File:Brain_fissure_development_02.jpg|500px]]

{|
| [[File:Gray0654.jpg|250px]]
| [[File:Gray0655.jpg|250px]]
| [[File:Gray0658.jpg|250px]]
|-
| Human brain at three months (median sagittal section)
| Human brain at four months (inferior surface)
| Human brain at five months (outer surface)
|}
During the fetal period there is ongoing growth in size, weight and surface area of the brain and spinal cord. Microscopically there is ongoing: cell migration, extension of processes, cell death and glial cell development.

Cortical maturation (sulcation and gyration) and vascularization of the lateral surface of the brain starts with the insular cortex (insula, insulary cortex or insular lobe) region during the fetal period. This cerebral cortex region in the adult brain lies deep within the lateral sulcus between the temporal lobe and the parietal lobe.

* '''sulcation''' - The process of brain growth in the second to third trimester which forms sulci, grooves or folds visible on fetal brain surface as gyri grow (gyration). Abnormalities of these processes can lead to a smooth brain (lissencephaly).
* '''gyration''' - The development of surface folds on the brain (singular, gyrus)

Insular Gyral and Sulcal Development

* 13-17 gestational weeks - appearance of the first sulcus
* 18-19 gestational weeks - development of the periinsular sulci
* 20-22 gestational weeks - central sulci and opercularization of the insula
* 24-26 gestational weeks - covering of the posterior insula
* 27-28 gestational weeks - closure of the laeteral sulcus (Sylvian fissure or lateral fissure)

(Data from<ref><pubmed>17962979</pubmed></ref>)

* Between 29-41 weeks volumes of: total brain, cerebral gray matter, unmyelinated white matter, myelinated, and cerebrospinal fluid (from MRI)
** grey matter- mainly neuronal cell bodies; white matter- mainly neural processes and glia.
* total brain tissue volume increased linearly over this period at a rate of 22 ml/week.
* Total grey matter also showed a linear increase in relative intracranial volume of approximately 1.4% or 15 ml/week.
* The rapid increase in total grey matter is mainly due to a fourfold increase in cortical grey matter.
* Quantification of extracerebral and intraventricular CSF was found to change only minimally.

(Text - modified from <ref><pubmed>9485064</pubmed></ref>)

Neural development will continue after birth with substantial glial development, growth, death and reorganization occuring during the postnatally.

:'''Links:''' [[Neural System - Fetal]] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=neurosci&part=A1465&rendertype=figure&id=A1466 Neuroscience - Regional specification of the developing brain]

==Thyroid System and Neural Development==

[[File:Human thyroid system and neural development.jpg|800px]]

Timeline of human thyroid system and brain development from conception to birth.<ref><pubmed>12060827</pubmed></ref> (Estimation of neurogenesis adapted from Bayer et al.<ref><pubmed>8361683</pubmed></ref>)

:'''Links:''' [[Endocrine - Thyroid Development]]

==References==

<references/>

==Movies==

[[Computed Tomography]]

{| border='0px'
|-
| [[File:Mouse_CT_E11.5_movie-icon.jpg|120px|link=Quicktime Movie_-_CT_Mouse_E11.5]]
| [[File:Adult human brain movie icon.jpg|120px|link=Quicktime_Movie_-_Adult_Brain]]
|-
| [[Quicktime Movie_-_CT_Mouse_E11.5|Mouse E11.5 microCT scan]]
| [[Quicktime_Movie_-_Adult_Brain|Human Adult Brain]]
|-
|}

[[Magnetic Resonance Imaging]]

{| border='0px'
|+ '''Human Embryo'''
|-
| [[File:Brain_fissure_development_03.jpg|90px|link=Quicktime Movie - Neural Sylvian Fissure‎‎]]
|-
| [[Quicktime Movie - Neural Sylvian Fissure‎‎|Neural Sylvian Fissure]]
|-
|}

==Historic Embryology==

* [[Book_-_Contributions_to_Embryology_Carnegie_Institution_No.59|Contributions to Embryology Carnegie Institution No.59]] Relative Weight and Volume of the Component Parts of the Brain of the Human Embryo at Different Stages of Development. Jenkins, G.B. (1921). pp5-54.

===Images===
Bailey, F.R. and Miller, A.M. (1921). Text-Book of Embryology. New York: William Wood and Co.

[[Book_-_Text-Book_of_Embryology_17|The nervous system]]

<gallery>
File:Bailey358.jpg|Fig. 358 A two-neurone reflex arc in a Vertebrate
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</gallery>

Gray, Henry. Anatomy of the Human Body. Philadelphia: Lea & Febiger, 1918.

<gallery>
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</gallery>

----

{{2012ANAT2341}}

{{Glossary}}

{{Footer}}

File:Endocrine Development.pdf

2013-10-07T03:53:35Z

Z3283213:

Lecture - Endocrine Development

2013-10-07T03:52:28Z

Z3283213:

==Introduction==
[[File:Week10 adrenal.jpg|thumb|300px|Human adrenal gland ([[Second_Trimester|Week 10]])]]
The endocrine system resides within specific endocrine organs and both organs and tissues with other specific functions. Epithelia (ectoderm and endoderm) form the majority of the “ductless” endocrine glands like gastrointestinal and skin associated “ducted” glands. Differentiation of several also organs involves a epithelial/mesenchye interaction, seen in repeated in many differentiation of many different tissues. The endocrine glands produce hormones, which are distributed by the vascular system to the many body tissues, subsequently these organs are richly vascularized.

Hormones “orchestrate” responses in other tissues, including other endocrine organs, and these overall effects can be similar or different in different tissues. These signaling pathways are often described as "axes" the two major types are the: '''HPA''' ('''H'''ypothalamus-'''P'''ituitary-'''A'''drenal) and '''HPG''' ('''H'''ypothalamus-'''P'''ituitary-'''G'''onad). These hormone effects (like music) can be rapid, slow, brief, diurnal, or long-term. Hormone effects can be mimicked, stimulated, and blocked by therapeutic drugs, nutritional and environmental chemicals. Importantly, fetal endocrine development is required for normal fetal growth and differentiation.

{|

{|
| [[File:Podcast icon.jpg]]
| --[[User:S8600021|Mark Hill]] 06:17, 26 September 2011 (EST) '''Interested in endocrine and hormone history?''' Listen to ABC Radio Ockham's Razor 2005-07-31 Centenary of the word "hormone" ([[File:Audio_-_centenary_of_hormone.mp3]]), by Sydney medical scientist (from SOMS) and writer Dr John Carmody commemorates the centenary of the entry of the word 'hormone' into the English language.
|}

==Lecture Objectives==
{|
| width="500px"|
* Understanding of hormone types
* Understanding of endocrine gland development
* Understanding of endocrine developmental functions

Lecture Date: 2013-10-08 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Endocrine Development.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

|}
| [[File:Historic-pituitary.jpg|200px]]
Historic drawing of the Pituitary.

|}

==Textbooks==
The endocrine "System" is not covered by a specific chapter in the embryology textbooks and you will need to look for related chapters on the development of individual components (some selected examples are listed below). Use the listed Endocrinology textbook for detained descriptions of function.
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Endocrine Links}} | [[2010_Lecture_17|2010 Lecture]]
|}

===Endocrinology - An Integrated Approach===
{|
| [[File:Endocrinology - An Integrated Approach.png|80px]]
| Nussey, S. and Whitehead, S. (2001). ''Endocrinology - An Integrated Approach''. UK Oxford: BIOS Scientific Publishers. ISBN-10: 1-85996-252-1.

[[Talk:Lecture_-_Endocrine_Development#Endocrinology_-_An_Integrated_Approach|Detailed Table of Contents]] | [http://www.ncbi.nlm.nih.gov/books/NBK22 Bookshelf Link]

* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A3/ Chapter 1. Principles of endocrinology]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A43/ Chapter 2. The endocrine pancreas]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/ Chapter 3. The thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A442/ Chapter 4. The adrenal gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A742/ Chapter 5. The parathyroid glands and vitamin D]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A972/ Chapter 6. The gonad]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A1257/ Chapter 7. The pituitary gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A1527/ Chapter 8. Cardiovascular and renal endocrinology]
|}

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00009-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00009-6 Chapter 9 – Pharyngeal Apparatus, Face, and Neck]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00012-6 Chapter 12 - Urogenital System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10016-8 Chapter 16 - Development of the Pharyngeal Apparatus and Face]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10015-6 Chapter 15 - Development of the Urogenital System]
|}

:'''Links:''' [[Embryology Textbooks]]

==Hormones==
[[File:Steroid hormone receptor signaling.jpg|thumb|Steroid hormone receptor signaling<ref><pubmed>17464358</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1853070 PMC1853070] | [http://www.nursa.org/article.cfm?doi=10.1621/nrs.05003 Nucl Recept Signal.]</ref>]]
===Hormone Types===
[[File:Steroid biosynthesis pathway.png|thumb|Steroid biosynthesis pathway]]
* '''Amino acid derivatives''' - noradrenaline (norepinepherine), adrenalin (epinepherine) , thyroid hormone
* '''Proteins, peptides''' - thyroid stimulating hormone, leutenising hormone, follicle stimulating hormone
* '''Steroids''' - androgens, glucocorticoids, mineralocorticoids

===Hormone Actions===
All hormones act upon cells in different tissues and can be classified by the "distance" of their action, the classical description is that hormones are delivered by the blood.

* '''Autocrine''' - acts on self (extracellular fluid).
* '''Paracrine''' - acts locally (extracellular fluid or blood).
* '''Endocrine''' - acts by secretion into blood stream (endocrine organs are richly vascularized).

===Hormone Receptors===
A cell or tissue can only directly respond to a hormone if it expresses a receptor for that hormone.

Hormone receptors are either:
# '''cell surface''' - modified amino acids, peptides, proteins.
# '''intracellular cytoplasmic/nuclear''' - steroids.

==Endocrine Origins==

* Derived from epithelia - covering embryo, lining gastrointestinal tract, lining coelomic cavity
* Also mesenchymal contribution

==Pineal Gland==
[[File:pineal-body.jpg|thumb|Adult pineal body]]
[[File:Pineal gland position.jpg|thumb|Pineal gland position]]

* part of epithalmus - neurons, glia and pinealocytes
* pinealocytes secrete melatonin - cyclic nature of activity, melatonin lowest during daylight
** inhibit hypothalamic secretion of GnRH until puberty, pineal gland then rapidly regresses.
* other activities - possibly gamete maturation, antioxidant effect, protect neurons?

===Pineal Development===
* Neuroectoderm - prosenecephalon then diencephalon
* caudal roof, median diverticulum, epiphysis
* Initially a hollow diverticulum, cell proliferation to solid, pinealocytes (neuroglia), cone-shaped gland innervated by epithalmus

:'''Links:''' [[Endocrine - Pineal Development]]
==Hypothalamus==

'''Hormones''' - Thyrotrophin releasing hormone (TRH), Corticotrophin releasing hormone (CRH), Arginine vasopressin (AVP), Gonadotrophin releasing hormone (GnRH), Growth hormone releasing hormone (GHRH), Somatostatin, Prolactin relasing factor (PRF), Dopamine

===Hypothalamus Development===
* Neuroectoderm - prosenecephalon then diencephalon
* ventro-lateral wall intermediate zone proliferation
* Mamillary bodies - form pea-sized swellings ventral wall of hypothalamus

:'''Links:''' [[Endocrine - Hypothalamus Development]]
==Pituitary==
[[File:Embryonic_and_fetal_pituitary.jpg]]
[[File:Historic-pituitary.jpg|thumb|Adult pituitary]]

'''Anterior pituitary hormones''' - Thyroid-stimulating hormone (TSH), Adrenocorticotrophic hormone (ACTH), Luteinizing hormone (LH), Follicle-stimulating hormone (FSH), Somatotrophin/growth hormone (GH), Prolactin (PRL), Melanocyte-stimulating hormone (MSH)

'''Posterior pituitary hormones''' - Oxytocin, Arginine vasopressin

===Pituitary Development===
[[File:Pituitary rabbit development.jpg|thumb|Pituitary rabbit development]]
{|
| [[File:Pituitary development animation.gif]]
| '''Blue''' - neural tube ectoderm

'''Red''' - surface ectoderm
|}

* Dual ectoderm origins
** Ectoderm - ectoderm roof of stomodeum, Rathke's pouch, adenohypophysis
** Neuroectoderm - prosenecephalon then diencephalon, neurohypophysis

'''Adenohypophysis'''
* Anterior wall proliferates - pars distalis
* Posterior wall little growth – pars intermedia
* Rostral growth around infundibular stem – pars tuberalis

'''Neurohypophysis'''
* Infundibulum – median eminence, infundibulum, pars nervosa

===Pituitary Timeline===
* '''Week 4''' - hypophysial pouch, Rathke’s pouch, diverticulum from roof
* '''Week 5''' - elongation, contacts infundibulum, diverticulum of diencephalon
* '''Week 6''' - connecting stalk between pouch and oral cavity degenerates
* '''Week 8''' - basophilic staining cells appear
* '''Week 9''' - acidophilic staining cells appear
* '''Week 10''' - growth hormone and ACTH detectable
* '''Week 16''' - adenohypophysis fully differentiated and TSH increases to peak at 22 weeks
* '''Week 20 to 24''' - growth hormone levels peak, then decline
* '''Birth''' - second TSH surge and decreases postnatally

:'''Links:''' [[Endocrine - Pituitary Development]] | [http://www.med.unc.edu/embryo_images/unit-nervous/nerv_htms/nerv016.htm Embryo Images - Pituitary] | [[Talk:Lecture - Endocrine Development#Chapter_7._The_pituitary_gland|Endocrinology]]

==Thyroid==
[[File:Stage13 and 22 thyroid development a.jpg|thumb|Stage 13 and Stage 22 thyroid development]]
* Functions from week 10, required for neural development, stimulates metabolism (protein, carbohydrate, lipid), reduced/absence = cretinism (see abnormalities)

'''Hormones''' - (amino acid derivatives) Thyroxine (T4), Triiodothyronine (T3)

===Thyroid Development===
{|
|
* thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* tongue grows, cells descend in neck
* thyroglossal duct - proximal end at the foramen cecum of tongue thyroglossal duct
* thyroid diverticulum - hollow then solid, right and left lobes, central isthmus
| [[File:Tongue1.png|thumb|foramen caecum]]
| [[File:Thyroid-development-cartoon.jpg|thumb|Thyroid development cartoon]]
|}
===Thyroid Timeline===
* 24 days - thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* Week 11 - colloid appearance in thyroid follicles, iodine and thyroid hormone (TH) synthesis
growth factors (insulin-like, epidermal) stimulates follicular growth

===Fetal Thyroid Hormone===
* Initial secreted biologically inactivated by modification, late fetal secretion develops brown fat
* Iodine deficiency- during this period, leads to neurological defects (cretinism)
* Birth - TSH levels increase, thyroxine (T3) and T4 levels increase to 24 h, then 5-7 days postnatal decline to normal levels

:'''Links:''' [[Endocrine - Thyroid Development]] | [[Abnormal_Development_-_Iodine_Deficiency|Iodine Deficiency]] | [[Talk:Lecture - Endocrine Development#Chapter_3._The_thyroid_gland|Endocrinology]]

==Parathyroid==
[[File:Parathyroid adult.jpg|thumb|Parathyroid adult]]

* Parathyroid Hormone - Increase calcium ions [Ca2+], stimulates osteoclasts, increase Ca GIT absorption (opposite effect to calcitonin)
* Adult Calcium and Phosphate - Daily turnover in human with dietary intake of 1000 mg/day
* secreted by chief cells
Principal cells cords of cells
===Parathyroid Development===
[[File:Pharyngeal pouches.jpg|thumb|Pharyngeal pouches]]
* Endoderm - third and fourth pharyngeal pouches, could also have ectoderm and neural crest
** 3rd Pharyngeal Pouch - inferior parathyroid, initially descends with thymus
** 4th Pharyngeal Pouch - superior parathyroid
* Week 6 - diverticulum elongate, hollow then solid, dorsal cell proliferation
* Fetal parathyroids - respond to calcium levels, fetal calcium levels higher than maternal

:'''Links:''' [[Endocrine - Parathyroid Development]]
==Thymus==

* Thymus - bone-marrow lymphocyte precursors become thymocytes, and subsequently mature into T lymphocytes (T cells)
* Thymus hormones - thymosins stimulate the development and differentiation of T lymphocytes

===Thymus Development===

* Endoderm - third pharyngeal pouch
* Week 6 - diverticulum elongates, hollow then solid, ventral cell proliferation
* Thymic primordia - surrounded by neural crest mesenchyme, epithelia/mesenchyme interaction

:'''Links:''' [[Endocrine - Thymus Development]]
==Pancreas==
[[File:Pancreas adult.jpg|thumb|Pancreas adult]]
[[File:Pancreas cartoon.jpg|thumb|pancreas structure]]

* Functions - exocrine (amylase, alpha-fetoprotein), 99% by volume; endocrine (pancreatic islets) 1% by volume
* Exocrine function - begins after birth
* Endocrine function - from 10 to 15 weeks onward hormone release
** exact roles of hormones in regulating fetal growth?

===Pancreas Development===
[[File:Pancreatic_duct_developing.jpg|thumb|Pancreatic buds and duct developing]]
[[File:Stage22_pancreas_a.jpg|thumb|Stage22 pancreas]]
* Pancreatic buds - duodenal level endoderm, splanchnic mesoderm forms dorsal and ventral mesentery, dorsal bud (larger, first), ventral bud (smaller, later)
* Pancreas Endoderm - pancreas may be opposite of liver
** Heart cells promote/notochord prevents liver formation
** Notochord may promote pancreas formation
** Heart may block pancreas formation

* Duodenum growth/rotation - brings ventral and dorsal buds together, fusion of buds
* Pancreatic duct - ventral bud duct and distal part of dorsal bud, exocrine function
* Islet cells - cords of endodermal cells form ducts, from which cells bud off to form islets

===Pancreatic Islets===
* Islets of Langerhans - 4 endocrine cell types
* '''Alpha''' - glucagon, mobilizes lipid
* '''Beta''' - insulin, increase glucose uptake
** Beta cells, stimulate fetal growth, continue to proliferate to postnatal, in infancy most abundant
* '''Delta''' - somatostatin, inhibits glucagon, insulin secretion
* '''F-cells''' - pancreatic polypeptide

===Pancreas Timeline===
* Week 7 to 20 - pancreatic hormones secretion increases, small amount maternal insulin
* Week 10 - glucagon (alpha) differentiate first, somatostatin (delta), insulin (beta) cells differentiate, insulin secretion begins
* Week 15 - glucagon detectable in fetal plasma

:'''Links:''' [[Endocrine - Pancreas Development]] | [[Gastrointestinal Tract - Pancreas Development]]
==Adrenal==

* Richly vascularized - arterioles passing through cortex, capillaries from cortex to medulla, portal-like circulation
* Fetal Cortex - produces a steroid precursor (DEA), converted by placenta into estrogen
* Adult Medulla - produces adrenalin (epinephrine), noradrenaline (norepinephrine)
* Fetal adrenal hormones - influence lung maturation

'''Adrenal cortical hormones''' - (steroids) Cortisol, Aldosterone, Dehydroepiandrosterone
* zona glomerulosa - regulated by renin-angiotensin-aldosterone system controlled by the juxtaglomerular apparatus of the kidney.
* zona fasciculata - regulated by hypothalamo-pituitary axis with the release of CRH and ACTH respectively.

'''Adrenal medullary hormones''' - (amino acid derivatives) Epinephrine, Norepinephrine

===Adrenal Development===
[[File:Week10 adrenal.jpg|thumb|Week 10 adrenal gland]]
{|
|
* Fetal Adrenals - fetal cortex later replaced by adult cortex
* Week 6 - fetal cortex, from mesothelium adjacent to dorsal mesentery; Medulla, neural crest cells from adjacent sympathetic ganglia
* Adult cortex - mesothelium mesenchyme encloses fetal cortex

'''Adrenal Cortex'''
* mesothelium origin, epithelium lining the body cavity at the site of adrenal development
* Late Fetal Period - differentiates to form cortical zones
* Birth - zona glomerulosa, zona fasiculata present
* Year 3 - zona reticularis present

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A442&rendertype=box&id=A466 Endocrinology - Adrenal Cortex Development]

'''Adrenal Medulla'''
* neural crest origin, migrate adjacent to coelomic cavity, initially uncapsulated and not surrounded by fetal cortex, cells have neuron-like morphology
* 2 cell types - secrete epinepherine (adrenaline) 80%; secrete norepinepherine (noradrenaline* 20%

| {{Adrenal movie}}
|}

:'''Links:''' [[Endocrine - Adrenal Development]]

==Gonad==
[[File:XXhpgaxis.gif|thumb|Female HPG axis]]

HPG Axis - [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A972&rendertype=box&id=A1057 Endocrinology - Simplified diagram of the actions of gonadotrophins]

===Gonad Development===
--[[User:S8600021|Mark Hill]] 07:31, 27 September 2011 (EST) Covered in last weeks [[Lecture_-_Genital_Development|lecture]] and [[2011_Lab_8|lab]].

* mesoderm - mesothelium and underlying mesenchyme, primordial germ cells
* Gonadal ridge - mesothelium thickening, medial mesonephros
* Primordial Germ cells - yolk sac, to mesentery of hindgut, to genital ridge of developing kidney

'''Differentiation'''
* testis-determining factor (TDF) from Y chromosome: presence (testes), absence (ovaries)

'''Testis'''
* 8 Weeks, mesenchyme, interstitial cells (of Leydig) secrete testosterone, androstenedione
* 8 to 12 Weeks - hCG stimulates testosterone production
* Sustentacular cells - produce anti-mullerian hormone to puberty

'''Ovary'''
* X chromosome genes regulate ovary development

:'''Links:''' [[Endocrine - Gonad Development]]

==Placenta==
[[File:Trophoblast hCG function.jpg|thumb|Trophoblast hCG function]]
* Human chorionic gonadotrophin (hCG) - like leutenizing hormone, supports corpus luteum in ovary, pregnant state rather than menstrual, maternal urine in some pregnancy testing

* Human chorionic somatommotropin (hCS) - or placental lactogen stimulate (maternal) mammary development
* Human chorionic thyrotropin (hCT)
* Human chorionic corticotropin (hCACTH)
* progesterone and estrogens - support maternal endometrium
* Relaxin

* Placenta - Maternal (decidua) and Fetal (trophoblastic cells, extraembryonic mesoderm) components
* Endocrine function - maternal and fetal precursors, synthesis and secretion
** Protein Hormones - chorionic gonadotropin (hCG), chorionic somatomammotropin (hCS) or placental lactogen (hPL), chorionic thyrotropin (hCT), chorionic corticotropin (hCACTH)
*** hCG - up to 20 weeks, fetal adrenal cortex growth and maintenance
*** hCS – rise through pregnancy, stimulates maternal metabolic processes, breast growth
** Steroid Hormones - progesterone (maintains pregnancy), estrogens (fetal adrenal/placenta)

:'''Links:''' [[Endocrine - Placenta Development]]
==Other Endocrine==
===Endocrine Heart===
* Atrial natriuretic peptide (ANP) - Increase Filtration rate / decrease Na+ reabsorption
* Endothelins - ET-1, ET-2, ET-3, Vasoconstriction / Increase NO
* Nitric oxide (NO) - Vasodilatation

===Endocrine Kidney===
* Renin - Increase Angiotensin-aldosterone system
* Prostaglandins - decrease Na+ reabsorption
* Erythropoietin - Increase Erythrocyte (rbc) production
* 1,25 (OH)2 vitamin D - calcium homeostasis
* Prekallikreins - Increase Kinin production

===GIT Endocrine===
Enteric control of digestive function
* Gastrin - Secreted from stomach (G cells), role in control of gastric acid secretion
* Cholecystokinin - small intestine hormone, stimulates secretion of pancreatic enzymes and bile
* Secretin - small intestine hormone (epithelial cells), stimulates secretion of bicarbonate-rich fluids from pancreas and liver

===Adipose Tissue===

* Leptin - polypeptide hormone produced in adipose and many other tissues with also many different roles
* Adiponectin - regulation of energy homeostasis and glucose and lipid metabolism, as well as acting as an anti-inflammatory on the cellular vascular wall
* Resistin - (for resistance to insulin, RETN) a 108 amino acid polypeptide and the related resistin-like protein-beta (Resistin-like molecule-beta, RELMbeta) stimulate endogenous glucose production

:'''Links:''' [[Endocrine - Other Tissues]]
==Endocrine Functional Changes==
* Puberty- Increased activity
* Menopause- Decreased activity
* Disease (diabetes, thyroid, kidney) suggested trends that genetics, health, nutrition, lifestyle may influence time that these events occur
* Pharmaceutical impact - birth control, steroids, Hormone Replacement Therapy (HRT)

==Abnormalities==
'''NIH Genes & Disease''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 Chapter 41 - Glands and Hormones]
===Pineal===
* hypoplasia - associated with retinal disease.
* tumours - in children are associated with abnormal puberty development.

===Pituitary===
* craniopharyngeal canal - Rathke's pouch abnormality, from the anterior part of the fossa hypophyseos of the sphenoid bone to the under surface of the skull.
* pituitary tumours (adenomas) - several abnormalities associated with abnormal levels of the hormonal output of the pituitary.
** Growth hormone (GH) adenomas - benign pituitary tumors lead to chronic high GH output levels, that may lead to acromegaly.
* Cushing's disease - caused either by a pituitary adenoma produces excess adrenocorticotropic hormone (ACTH, corticotropin) or due to ectopic tumors secreting ACTH or corticotropin-releasing hormone (CRH).

=== Thyroid ===
[[File:Thyroid_pyramidal_lobe.jpg|thumb|Thyroid pyramidal lobe]]
[[File:Thyroid uptake scans .jpg|thumb|Thyroid uptake scans]]
* Pyramidal lobe - from isthmus (50% of people) attached to hyoid bone distal end of thryoglossal duct.
* Congenital hypothyroidism - approximately 1 in 3000 births, associated with neurological abnormalities.
* Lingual thyroid gland - failure of thyroid descent.
* Thyroglossal cyst - persistance of thyroglossal duct. [http://www.upstate.edu/cdb/grossanat/imgs/tgdfig2.jpg Image - thyroglossal duct]
* Thyroglossal fistula - partial degeneration of the thyroglossal duct.
* Abnormal development of the thyroid - incomplete or excessive descent.
* Childhood hypothyroidism delays ossification and bone mineralization.

Iodine Deficiency
* A teaspoon of iodine, total lifetime requirement, cannot be stored for long periods by our body, tiny amounts are needed regularly
* Areas of endemic iodine deficiency, where soil and therefore crops and grazing animals do not provide sufficient dietary iodine to the populace
* food fortification and supplementation - Iodized salt programs and iodized oil supplements are the most common tools in fight against IDD

===Parathyroid===
* Usually four glands are present (2 on each side), but three to six glands have been found in human.
* Lower parathyroid glands arise from the third pharyngeal pouch and descend with the thymus. Variable descent can lead to a range of adult locations, from just beneath the mandible to the anterior mediastinum.

===Pancreas===
* Type 1 Diabetes - juvenile onset diabetes, more severe form of illness, increases risk of blindness, heart disease, kidney failure, neurological disease, T-lymphocyte-dependent autoimmune disease, infiltration and destruction of the islets of Langerhans, Approx 16 million Americans
* Type 2 Diabetes - loosely defined as "adult onset" diabetes, becoming more common cases of type 2 diabetes seen in younger people
* Risk of developing diabetes - environmental factors (food intake and exercise play an important role, either overweight or obese), Inherited factors (genes involved remain poorly defined)

===Adrenal===
* Congenital Adrenal Hyperplasia (CAH) - family of inherited disorders of adrenal steroidogenesis enzymes which impairs cortisol production by the adrenal cortex. Androgen excess leads newborn females with external genital ambiguity and postnatal progressive virilization in both sexes.
** Enzymes most commonly affected: 21-hydroxylase (21-OH), 11beta-hydroxylase, 3beta-hydroxysteroid dehydrogenase.
** Enzymes less commonly affected: 17alpha-hydroxylase/17,20-lyase and cholesterol desmolase.

* Pheochromocytomas (PCC) - Catecholamine-producing (neuro)endocrine tumor located in the adrenal medulla. Similar catecholamine-producing tumors outside the adrenal gland are called paragangliomas (PGL).

===Endocrine Disruptors===
Exogenous chemicals that interfere with the function of hormones. There are 3 main mechanisms: mimic, block or interfere.

'''Mimic''' - effects of natural hormones by binding receptors
* Diethylstilbestrol - (DES or diethylstilbetrol) a drug prescribed to women from 1938-1971 to prevent miscarriage in high-risk pregnancies. Acts as a potent estrogen (mimics natural hormone) and therefore a potential endocrine disruptor. Female fetus, increased risk abnormal reproductive tract and cancer. Male fetus, abnormal genitalia. Banned by USA FDA in 1979 as a teratogen, previously used as livestock growth promoter.

'''Block''' - binding of a hormone to receptor or hormone synthesis
* Finasteride - chemical used to prevent male pattern baldness and enlargement of prostate glands. An anti-androgen (blocks synthesis of dihydrotestosterone) and therefore a potential endocrine disruptor, exposed pregnant women can impact on male fetus genetial development.
* Vinclozolin - a dicarboximide fungicide, perinatal exposure in rats inhibits morphological sex differentiation. In adult rats, shown to cause gonad tumours (Leydig cell) and atrophy. Chemical has androgen-antagonist (antiandrogenic) activity, metabolies compete with natural androgen

'''Interfere''' - with hormone transport or elimination

* Polychlorinated biphenyl pollutants - (PCBs) Rats exposed to PCBs have low levels of thyroid hormone. Compete for binding sites of thyroid hormone transport protein. Without being bound to this protein, thyroid hormones are excreted from the body (McKinney et al. 1985; Morse et al. 1996)

==References==
<references/>

* Endocrinology: An Integrated Approach Nussey, S.S. and Whitehead, S.A. London:Taylor & Francis; c2001 [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A3&rendertype=box&id=A11 Major hormone types]
* Genes and Disease, Bethesda (MD): National Library of Medicine (US), NCBI [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 Chapter 41 - Glands and Hormones]
===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=endocrine endocrine] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=pineal_gland pineal gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=hypothalmus hypothalamus] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=pituitary_gland pituitary gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=thyroid_gland thyroid gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=parathyroid_gland parathyroid gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=thymus_gland thymus gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=endocrine_pancreas endocrine pancreas] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=adrenal_gland adrenal gland]
* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=endocrine_development endocrine development]

==Histology==
===Adult===
<gallery>
File:Pineal_histology_001.jpg|Pineal (high power)
File:Thyroid_histology_001.jpg|Thyroid (low power)
File:Thyroid_histology_002.jpg|Thyroid (high power)
File:Parathyroid_histology_001.jpg|Parathyroid (low power)
File:Parathyroid_histology_002.jpg|Parathyroid (high power)
File:Pituitary histology 001.jpg|Pituitary - adenohypophysis
File:Pituitary histology 002.jpg|Pituitary - adenohypophysis
File:Pituitary histology 003.jpg|Pituitary - neurohypophysis
File:Adrenal histology 001.jpg|Adrenal - Cortex and Medulla
File:Adrenal histology 002.jpg|Adrenal - Cortical Zones
File:Adrenal histology 003.jpg|Adrenal - Zona Reticularis and Medulla
File:Pancreatic islet.png|Pancreatic islet
</gallery>

===Embryonic===
<gallery>

File:Stage22_pancreas_b.jpg|Stage 22 - Pancreatic duct
File:Stage22 adrenal.jpg|Stage 22 - Adrenal gland
File:Week10 adrenal.jpg|Week 10 - Adrenal gland
</gallery>

==Terms==

'''adrenocorticotropin''' - (ACTH or corticotropin) anterior pituitary, peptide hormone

'''antidiuretic hormone''' - (ADH) hypothalamus, peptide hormone

'''atrial natriuretic factor''' - (ANP) heart, , peptide hormone

'''calcitonin''' - (CT) C cells of thyroid, peptide hormone

'''follicle stimulating hormone''' - (FSH) pituitary, protein hormone

'''growth hormone''' - (GH) pituitary, peptide hormone

'''human chorionic gonadotropin''' - (hCG) pancreas glycoprotein hormone with 2 subunits (alpha and beta joined non covalently). Similar in structure to luteinizing hormone (LH), hCG exists in multiple hormonal and non-endocrine agents (regular hCG, hyperglycosylated hCG and the free beta-subunit of hyperglycosylated hCG). [http://www.ncbi.nlm.nih.gov/pubmed/19171054 PMID: 19171054]

'''lutenizing hormone''' - (LH) pituitary, protein hormone

'''melaocyte stimulating hormone''' - (MSH) pituitary, peptide hormone

'''prolactin''' - (PRL) pituitary, peptide hormone

'''parathyroid hormone''' - (PTH) parathyroid, peptide hormone

'''thyroid hormone''' - (TH) thyroid,amino acid derivative

'''thyroid stimulating hormone''' - (TSH) pituitary, protein hormone

[[Category:Endocrine]] [[Category:Adrenal]] [[Category:Thyroid]] [[Category:Parathyroid]] [[Category:Pituitary]] [[Category:Pancreas]] [[Category:Genital]]

{{2012ANAT2341}}

Lecture - Endocrine Development

2013-10-07T03:51:42Z

Z3283213:

==Introduction==
[[File:Week10 adrenal.jpg|thumb|300px|Human adrenal gland ([[Second_Trimester|Week 10]])]]
The endocrine system resides within specific endocrine organs and both organs and tissues with other specific functions. Epithelia (ectoderm and endoderm) form the majority of the “ductless” endocrine glands like gastrointestinal and skin associated “ducted” glands. Differentiation of several also organs involves a epithelial/mesenchye interaction, seen in repeated in many differentiation of many different tissues. The endocrine glands produce hormones, which are distributed by the vascular system to the many body tissues, subsequently these organs are richly vascularized.

Hormones “orchestrate” responses in other tissues, including other endocrine organs, and these overall effects can be similar or different in different tissues. These signaling pathways are often described as "axes" the two major types are the: '''HPA''' ('''H'''ypothalamus-'''P'''ituitary-'''A'''drenal) and '''HPG''' ('''H'''ypothalamus-'''P'''ituitary-'''G'''onad). These hormone effects (like music) can be rapid, slow, brief, diurnal, or long-term. Hormone effects can be mimicked, stimulated, and blocked by therapeutic drugs, nutritional and environmental chemicals. Importantly, fetal endocrine development is required for normal fetal growth and differentiation.

{|

{|
| [[File:Podcast icon.jpg]]
| --[[User:S8600021|Mark Hill]] 06:17, 26 September 2011 (EST) '''Interested in endocrine and hormone history?''' Listen to ABC Radio Ockham's Razor 2005-07-31 Centenary of the word "hormone" ([[File:Audio_-_centenary_of_hormone.mp3]]), by Sydney medical scientist (from SOMS) and writer Dr John Carmody commemorates the centenary of the entry of the word 'hormone' into the English language.
|}

==Lecture Objectives==
{|
| width="500px"|
* Understanding of hormone types
* Understanding of endocrine gland development
* Understanding of endocrine developmental functions

Lecture Date: 2013-10-08 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Endocrine Development.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

Historic drawing of the Pituitary.
| [[File:Historic-pituitary.jpg|200px]]
|}

==Textbooks==
The endocrine "System" is not covered by a specific chapter in the embryology textbooks and you will need to look for related chapters on the development of individual components (some selected examples are listed below). Use the listed Endocrinology textbook for detained descriptions of function.
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Endocrine Links}} | [[2010_Lecture_17|2010 Lecture]]
|}

===Endocrinology - An Integrated Approach===
{|
| [[File:Endocrinology - An Integrated Approach.png|80px]]
| Nussey, S. and Whitehead, S. (2001). ''Endocrinology - An Integrated Approach''. UK Oxford: BIOS Scientific Publishers. ISBN-10: 1-85996-252-1.

[[Talk:Lecture_-_Endocrine_Development#Endocrinology_-_An_Integrated_Approach|Detailed Table of Contents]] | [http://www.ncbi.nlm.nih.gov/books/NBK22 Bookshelf Link]

* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A3/ Chapter 1. Principles of endocrinology]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A43/ Chapter 2. The endocrine pancreas]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/ Chapter 3. The thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A442/ Chapter 4. The adrenal gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A742/ Chapter 5. The parathyroid glands and vitamin D]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A972/ Chapter 6. The gonad]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A1257/ Chapter 7. The pituitary gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A1527/ Chapter 8. Cardiovascular and renal endocrinology]
|}

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00009-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00009-6 Chapter 9 – Pharyngeal Apparatus, Face, and Neck]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00012-6 Chapter 12 - Urogenital System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10016-8 Chapter 16 - Development of the Pharyngeal Apparatus and Face]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10015-6 Chapter 15 - Development of the Urogenital System]
|}

:'''Links:''' [[Embryology Textbooks]]

==Hormones==
[[File:Steroid hormone receptor signaling.jpg|thumb|Steroid hormone receptor signaling<ref><pubmed>17464358</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1853070 PMC1853070] | [http://www.nursa.org/article.cfm?doi=10.1621/nrs.05003 Nucl Recept Signal.]</ref>]]
===Hormone Types===
[[File:Steroid biosynthesis pathway.png|thumb|Steroid biosynthesis pathway]]
* '''Amino acid derivatives''' - noradrenaline (norepinepherine), adrenalin (epinepherine) , thyroid hormone
* '''Proteins, peptides''' - thyroid stimulating hormone, leutenising hormone, follicle stimulating hormone
* '''Steroids''' - androgens, glucocorticoids, mineralocorticoids

===Hormone Actions===
All hormones act upon cells in different tissues and can be classified by the "distance" of their action, the classical description is that hormones are delivered by the blood.

* '''Autocrine''' - acts on self (extracellular fluid).
* '''Paracrine''' - acts locally (extracellular fluid or blood).
* '''Endocrine''' - acts by secretion into blood stream (endocrine organs are richly vascularized).

===Hormone Receptors===
A cell or tissue can only directly respond to a hormone if it expresses a receptor for that hormone.

Hormone receptors are either:
# '''cell surface''' - modified amino acids, peptides, proteins.
# '''intracellular cytoplasmic/nuclear''' - steroids.

==Endocrine Origins==

* Derived from epithelia - covering embryo, lining gastrointestinal tract, lining coelomic cavity
* Also mesenchymal contribution

==Pineal Gland==
[[File:pineal-body.jpg|thumb|Adult pineal body]]
[[File:Pineal gland position.jpg|thumb|Pineal gland position]]

* part of epithalmus - neurons, glia and pinealocytes
* pinealocytes secrete melatonin - cyclic nature of activity, melatonin lowest during daylight
** inhibit hypothalamic secretion of GnRH until puberty, pineal gland then rapidly regresses.
* other activities - possibly gamete maturation, antioxidant effect, protect neurons?

===Pineal Development===
* Neuroectoderm - prosenecephalon then diencephalon
* caudal roof, median diverticulum, epiphysis
* Initially a hollow diverticulum, cell proliferation to solid, pinealocytes (neuroglia), cone-shaped gland innervated by epithalmus

:'''Links:''' [[Endocrine - Pineal Development]]
==Hypothalamus==

'''Hormones''' - Thyrotrophin releasing hormone (TRH), Corticotrophin releasing hormone (CRH), Arginine vasopressin (AVP), Gonadotrophin releasing hormone (GnRH), Growth hormone releasing hormone (GHRH), Somatostatin, Prolactin relasing factor (PRF), Dopamine

===Hypothalamus Development===
* Neuroectoderm - prosenecephalon then diencephalon
* ventro-lateral wall intermediate zone proliferation
* Mamillary bodies - form pea-sized swellings ventral wall of hypothalamus

:'''Links:''' [[Endocrine - Hypothalamus Development]]
==Pituitary==
[[File:Embryonic_and_fetal_pituitary.jpg]]
[[File:Historic-pituitary.jpg|thumb|Adult pituitary]]

'''Anterior pituitary hormones''' - Thyroid-stimulating hormone (TSH), Adrenocorticotrophic hormone (ACTH), Luteinizing hormone (LH), Follicle-stimulating hormone (FSH), Somatotrophin/growth hormone (GH), Prolactin (PRL), Melanocyte-stimulating hormone (MSH)

'''Posterior pituitary hormones''' - Oxytocin, Arginine vasopressin

===Pituitary Development===
[[File:Pituitary rabbit development.jpg|thumb|Pituitary rabbit development]]
{|
| [[File:Pituitary development animation.gif]]
| '''Blue''' - neural tube ectoderm

'''Red''' - surface ectoderm
|}

* Dual ectoderm origins
** Ectoderm - ectoderm roof of stomodeum, Rathke's pouch, adenohypophysis
** Neuroectoderm - prosenecephalon then diencephalon, neurohypophysis

'''Adenohypophysis'''
* Anterior wall proliferates - pars distalis
* Posterior wall little growth – pars intermedia
* Rostral growth around infundibular stem – pars tuberalis

'''Neurohypophysis'''
* Infundibulum – median eminence, infundibulum, pars nervosa

===Pituitary Timeline===
* '''Week 4''' - hypophysial pouch, Rathke’s pouch, diverticulum from roof
* '''Week 5''' - elongation, contacts infundibulum, diverticulum of diencephalon
* '''Week 6''' - connecting stalk between pouch and oral cavity degenerates
* '''Week 8''' - basophilic staining cells appear
* '''Week 9''' - acidophilic staining cells appear
* '''Week 10''' - growth hormone and ACTH detectable
* '''Week 16''' - adenohypophysis fully differentiated and TSH increases to peak at 22 weeks
* '''Week 20 to 24''' - growth hormone levels peak, then decline
* '''Birth''' - second TSH surge and decreases postnatally

:'''Links:''' [[Endocrine - Pituitary Development]] | [http://www.med.unc.edu/embryo_images/unit-nervous/nerv_htms/nerv016.htm Embryo Images - Pituitary] | [[Talk:Lecture - Endocrine Development#Chapter_7._The_pituitary_gland|Endocrinology]]

==Thyroid==
[[File:Stage13 and 22 thyroid development a.jpg|thumb|Stage 13 and Stage 22 thyroid development]]
* Functions from week 10, required for neural development, stimulates metabolism (protein, carbohydrate, lipid), reduced/absence = cretinism (see abnormalities)

'''Hormones''' - (amino acid derivatives) Thyroxine (T4), Triiodothyronine (T3)

===Thyroid Development===
{|
|
* thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* tongue grows, cells descend in neck
* thyroglossal duct - proximal end at the foramen cecum of tongue thyroglossal duct
* thyroid diverticulum - hollow then solid, right and left lobes, central isthmus
| [[File:Tongue1.png|thumb|foramen caecum]]
| [[File:Thyroid-development-cartoon.jpg|thumb|Thyroid development cartoon]]
|}
===Thyroid Timeline===
* 24 days - thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* Week 11 - colloid appearance in thyroid follicles, iodine and thyroid hormone (TH) synthesis
growth factors (insulin-like, epidermal) stimulates follicular growth

===Fetal Thyroid Hormone===
* Initial secreted biologically inactivated by modification, late fetal secretion develops brown fat
* Iodine deficiency- during this period, leads to neurological defects (cretinism)
* Birth - TSH levels increase, thyroxine (T3) and T4 levels increase to 24 h, then 5-7 days postnatal decline to normal levels

:'''Links:''' [[Endocrine - Thyroid Development]] | [[Abnormal_Development_-_Iodine_Deficiency|Iodine Deficiency]] | [[Talk:Lecture - Endocrine Development#Chapter_3._The_thyroid_gland|Endocrinology]]

==Parathyroid==
[[File:Parathyroid adult.jpg|thumb|Parathyroid adult]]

* Parathyroid Hormone - Increase calcium ions [Ca2+], stimulates osteoclasts, increase Ca GIT absorption (opposite effect to calcitonin)
* Adult Calcium and Phosphate - Daily turnover in human with dietary intake of 1000 mg/day
* secreted by chief cells
Principal cells cords of cells
===Parathyroid Development===
[[File:Pharyngeal pouches.jpg|thumb|Pharyngeal pouches]]
* Endoderm - third and fourth pharyngeal pouches, could also have ectoderm and neural crest
** 3rd Pharyngeal Pouch - inferior parathyroid, initially descends with thymus
** 4th Pharyngeal Pouch - superior parathyroid
* Week 6 - diverticulum elongate, hollow then solid, dorsal cell proliferation
* Fetal parathyroids - respond to calcium levels, fetal calcium levels higher than maternal

:'''Links:''' [[Endocrine - Parathyroid Development]]
==Thymus==

* Thymus - bone-marrow lymphocyte precursors become thymocytes, and subsequently mature into T lymphocytes (T cells)
* Thymus hormones - thymosins stimulate the development and differentiation of T lymphocytes

===Thymus Development===

* Endoderm - third pharyngeal pouch
* Week 6 - diverticulum elongates, hollow then solid, ventral cell proliferation
* Thymic primordia - surrounded by neural crest mesenchyme, epithelia/mesenchyme interaction

:'''Links:''' [[Endocrine - Thymus Development]]
==Pancreas==
[[File:Pancreas adult.jpg|thumb|Pancreas adult]]
[[File:Pancreas cartoon.jpg|thumb|pancreas structure]]

* Functions - exocrine (amylase, alpha-fetoprotein), 99% by volume; endocrine (pancreatic islets) 1% by volume
* Exocrine function - begins after birth
* Endocrine function - from 10 to 15 weeks onward hormone release
** exact roles of hormones in regulating fetal growth?

===Pancreas Development===
[[File:Pancreatic_duct_developing.jpg|thumb|Pancreatic buds and duct developing]]
[[File:Stage22_pancreas_a.jpg|thumb|Stage22 pancreas]]
* Pancreatic buds - duodenal level endoderm, splanchnic mesoderm forms dorsal and ventral mesentery, dorsal bud (larger, first), ventral bud (smaller, later)
* Pancreas Endoderm - pancreas may be opposite of liver
** Heart cells promote/notochord prevents liver formation
** Notochord may promote pancreas formation
** Heart may block pancreas formation

* Duodenum growth/rotation - brings ventral and dorsal buds together, fusion of buds
* Pancreatic duct - ventral bud duct and distal part of dorsal bud, exocrine function
* Islet cells - cords of endodermal cells form ducts, from which cells bud off to form islets

===Pancreatic Islets===
* Islets of Langerhans - 4 endocrine cell types
* '''Alpha''' - glucagon, mobilizes lipid
* '''Beta''' - insulin, increase glucose uptake
** Beta cells, stimulate fetal growth, continue to proliferate to postnatal, in infancy most abundant
* '''Delta''' - somatostatin, inhibits glucagon, insulin secretion
* '''F-cells''' - pancreatic polypeptide

===Pancreas Timeline===
* Week 7 to 20 - pancreatic hormones secretion increases, small amount maternal insulin
* Week 10 - glucagon (alpha) differentiate first, somatostatin (delta), insulin (beta) cells differentiate, insulin secretion begins
* Week 15 - glucagon detectable in fetal plasma

:'''Links:''' [[Endocrine - Pancreas Development]] | [[Gastrointestinal Tract - Pancreas Development]]
==Adrenal==

* Richly vascularized - arterioles passing through cortex, capillaries from cortex to medulla, portal-like circulation
* Fetal Cortex - produces a steroid precursor (DEA), converted by placenta into estrogen
* Adult Medulla - produces adrenalin (epinephrine), noradrenaline (norepinephrine)
* Fetal adrenal hormones - influence lung maturation

'''Adrenal cortical hormones''' - (steroids) Cortisol, Aldosterone, Dehydroepiandrosterone
* zona glomerulosa - regulated by renin-angiotensin-aldosterone system controlled by the juxtaglomerular apparatus of the kidney.
* zona fasciculata - regulated by hypothalamo-pituitary axis with the release of CRH and ACTH respectively.

'''Adrenal medullary hormones''' - (amino acid derivatives) Epinephrine, Norepinephrine

===Adrenal Development===
[[File:Week10 adrenal.jpg|thumb|Week 10 adrenal gland]]
{|
|
* Fetal Adrenals - fetal cortex later replaced by adult cortex
* Week 6 - fetal cortex, from mesothelium adjacent to dorsal mesentery; Medulla, neural crest cells from adjacent sympathetic ganglia
* Adult cortex - mesothelium mesenchyme encloses fetal cortex

'''Adrenal Cortex'''
* mesothelium origin, epithelium lining the body cavity at the site of adrenal development
* Late Fetal Period - differentiates to form cortical zones
* Birth - zona glomerulosa, zona fasiculata present
* Year 3 - zona reticularis present

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A442&rendertype=box&id=A466 Endocrinology - Adrenal Cortex Development]

'''Adrenal Medulla'''
* neural crest origin, migrate adjacent to coelomic cavity, initially uncapsulated and not surrounded by fetal cortex, cells have neuron-like morphology
* 2 cell types - secrete epinepherine (adrenaline) 80%; secrete norepinepherine (noradrenaline* 20%

| {{Adrenal movie}}
|}

:'''Links:''' [[Endocrine - Adrenal Development]]

==Gonad==
[[File:XXhpgaxis.gif|thumb|Female HPG axis]]

HPG Axis - [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A972&rendertype=box&id=A1057 Endocrinology - Simplified diagram of the actions of gonadotrophins]

===Gonad Development===
--[[User:S8600021|Mark Hill]] 07:31, 27 September 2011 (EST) Covered in last weeks [[Lecture_-_Genital_Development|lecture]] and [[2011_Lab_8|lab]].

* mesoderm - mesothelium and underlying mesenchyme, primordial germ cells
* Gonadal ridge - mesothelium thickening, medial mesonephros
* Primordial Germ cells - yolk sac, to mesentery of hindgut, to genital ridge of developing kidney

'''Differentiation'''
* testis-determining factor (TDF) from Y chromosome: presence (testes), absence (ovaries)

'''Testis'''
* 8 Weeks, mesenchyme, interstitial cells (of Leydig) secrete testosterone, androstenedione
* 8 to 12 Weeks - hCG stimulates testosterone production
* Sustentacular cells - produce anti-mullerian hormone to puberty

'''Ovary'''
* X chromosome genes regulate ovary development

:'''Links:''' [[Endocrine - Gonad Development]]

==Placenta==
[[File:Trophoblast hCG function.jpg|thumb|Trophoblast hCG function]]
* Human chorionic gonadotrophin (hCG) - like leutenizing hormone, supports corpus luteum in ovary, pregnant state rather than menstrual, maternal urine in some pregnancy testing

* Human chorionic somatommotropin (hCS) - or placental lactogen stimulate (maternal) mammary development
* Human chorionic thyrotropin (hCT)
* Human chorionic corticotropin (hCACTH)
* progesterone and estrogens - support maternal endometrium
* Relaxin

* Placenta - Maternal (decidua) and Fetal (trophoblastic cells, extraembryonic mesoderm) components
* Endocrine function - maternal and fetal precursors, synthesis and secretion
** Protein Hormones - chorionic gonadotropin (hCG), chorionic somatomammotropin (hCS) or placental lactogen (hPL), chorionic thyrotropin (hCT), chorionic corticotropin (hCACTH)
*** hCG - up to 20 weeks, fetal adrenal cortex growth and maintenance
*** hCS – rise through pregnancy, stimulates maternal metabolic processes, breast growth
** Steroid Hormones - progesterone (maintains pregnancy), estrogens (fetal adrenal/placenta)

:'''Links:''' [[Endocrine - Placenta Development]]
==Other Endocrine==
===Endocrine Heart===
* Atrial natriuretic peptide (ANP) - Increase Filtration rate / decrease Na+ reabsorption
* Endothelins - ET-1, ET-2, ET-3, Vasoconstriction / Increase NO
* Nitric oxide (NO) - Vasodilatation

===Endocrine Kidney===
* Renin - Increase Angiotensin-aldosterone system
* Prostaglandins - decrease Na+ reabsorption
* Erythropoietin - Increase Erythrocyte (rbc) production
* 1,25 (OH)2 vitamin D - calcium homeostasis
* Prekallikreins - Increase Kinin production

===GIT Endocrine===
Enteric control of digestive function
* Gastrin - Secreted from stomach (G cells), role in control of gastric acid secretion
* Cholecystokinin - small intestine hormone, stimulates secretion of pancreatic enzymes and bile
* Secretin - small intestine hormone (epithelial cells), stimulates secretion of bicarbonate-rich fluids from pancreas and liver

===Adipose Tissue===

* Leptin - polypeptide hormone produced in adipose and many other tissues with also many different roles
* Adiponectin - regulation of energy homeostasis and glucose and lipid metabolism, as well as acting as an anti-inflammatory on the cellular vascular wall
* Resistin - (for resistance to insulin, RETN) a 108 amino acid polypeptide and the related resistin-like protein-beta (Resistin-like molecule-beta, RELMbeta) stimulate endogenous glucose production

:'''Links:''' [[Endocrine - Other Tissues]]
==Endocrine Functional Changes==
* Puberty- Increased activity
* Menopause- Decreased activity
* Disease (diabetes, thyroid, kidney) suggested trends that genetics, health, nutrition, lifestyle may influence time that these events occur
* Pharmaceutical impact - birth control, steroids, Hormone Replacement Therapy (HRT)

==Abnormalities==
'''NIH Genes & Disease''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 Chapter 41 - Glands and Hormones]
===Pineal===
* hypoplasia - associated with retinal disease.
* tumours - in children are associated with abnormal puberty development.

===Pituitary===
* craniopharyngeal canal - Rathke's pouch abnormality, from the anterior part of the fossa hypophyseos of the sphenoid bone to the under surface of the skull.
* pituitary tumours (adenomas) - several abnormalities associated with abnormal levels of the hormonal output of the pituitary.
** Growth hormone (GH) adenomas - benign pituitary tumors lead to chronic high GH output levels, that may lead to acromegaly.
* Cushing's disease - caused either by a pituitary adenoma produces excess adrenocorticotropic hormone (ACTH, corticotropin) or due to ectopic tumors secreting ACTH or corticotropin-releasing hormone (CRH).

=== Thyroid ===
[[File:Thyroid_pyramidal_lobe.jpg|thumb|Thyroid pyramidal lobe]]
[[File:Thyroid uptake scans .jpg|thumb|Thyroid uptake scans]]
* Pyramidal lobe - from isthmus (50% of people) attached to hyoid bone distal end of thryoglossal duct.
* Congenital hypothyroidism - approximately 1 in 3000 births, associated with neurological abnormalities.
* Lingual thyroid gland - failure of thyroid descent.
* Thyroglossal cyst - persistance of thyroglossal duct. [http://www.upstate.edu/cdb/grossanat/imgs/tgdfig2.jpg Image - thyroglossal duct]
* Thyroglossal fistula - partial degeneration of the thyroglossal duct.
* Abnormal development of the thyroid - incomplete or excessive descent.
* Childhood hypothyroidism delays ossification and bone mineralization.

Iodine Deficiency
* A teaspoon of iodine, total lifetime requirement, cannot be stored for long periods by our body, tiny amounts are needed regularly
* Areas of endemic iodine deficiency, where soil and therefore crops and grazing animals do not provide sufficient dietary iodine to the populace
* food fortification and supplementation - Iodized salt programs and iodized oil supplements are the most common tools in fight against IDD

===Parathyroid===
* Usually four glands are present (2 on each side), but three to six glands have been found in human.
* Lower parathyroid glands arise from the third pharyngeal pouch and descend with the thymus. Variable descent can lead to a range of adult locations, from just beneath the mandible to the anterior mediastinum.

===Pancreas===
* Type 1 Diabetes - juvenile onset diabetes, more severe form of illness, increases risk of blindness, heart disease, kidney failure, neurological disease, T-lymphocyte-dependent autoimmune disease, infiltration and destruction of the islets of Langerhans, Approx 16 million Americans
* Type 2 Diabetes - loosely defined as "adult onset" diabetes, becoming more common cases of type 2 diabetes seen in younger people
* Risk of developing diabetes - environmental factors (food intake and exercise play an important role, either overweight or obese), Inherited factors (genes involved remain poorly defined)

===Adrenal===
* Congenital Adrenal Hyperplasia (CAH) - family of inherited disorders of adrenal steroidogenesis enzymes which impairs cortisol production by the adrenal cortex. Androgen excess leads newborn females with external genital ambiguity and postnatal progressive virilization in both sexes.
** Enzymes most commonly affected: 21-hydroxylase (21-OH), 11beta-hydroxylase, 3beta-hydroxysteroid dehydrogenase.
** Enzymes less commonly affected: 17alpha-hydroxylase/17,20-lyase and cholesterol desmolase.

* Pheochromocytomas (PCC) - Catecholamine-producing (neuro)endocrine tumor located in the adrenal medulla. Similar catecholamine-producing tumors outside the adrenal gland are called paragangliomas (PGL).

===Endocrine Disruptors===
Exogenous chemicals that interfere with the function of hormones. There are 3 main mechanisms: mimic, block or interfere.

'''Mimic''' - effects of natural hormones by binding receptors
* Diethylstilbestrol - (DES or diethylstilbetrol) a drug prescribed to women from 1938-1971 to prevent miscarriage in high-risk pregnancies. Acts as a potent estrogen (mimics natural hormone) and therefore a potential endocrine disruptor. Female fetus, increased risk abnormal reproductive tract and cancer. Male fetus, abnormal genitalia. Banned by USA FDA in 1979 as a teratogen, previously used as livestock growth promoter.

'''Block''' - binding of a hormone to receptor or hormone synthesis
* Finasteride - chemical used to prevent male pattern baldness and enlargement of prostate glands. An anti-androgen (blocks synthesis of dihydrotestosterone) and therefore a potential endocrine disruptor, exposed pregnant women can impact on male fetus genetial development.
* Vinclozolin - a dicarboximide fungicide, perinatal exposure in rats inhibits morphological sex differentiation. In adult rats, shown to cause gonad tumours (Leydig cell) and atrophy. Chemical has androgen-antagonist (antiandrogenic) activity, metabolies compete with natural androgen

'''Interfere''' - with hormone transport or elimination

* Polychlorinated biphenyl pollutants - (PCBs) Rats exposed to PCBs have low levels of thyroid hormone. Compete for binding sites of thyroid hormone transport protein. Without being bound to this protein, thyroid hormones are excreted from the body (McKinney et al. 1985; Morse et al. 1996)

==References==
<references/>

* Endocrinology: An Integrated Approach Nussey, S.S. and Whitehead, S.A. London:Taylor & Francis; c2001 [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A3&rendertype=box&id=A11 Major hormone types]
* Genes and Disease, Bethesda (MD): National Library of Medicine (US), NCBI [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 Chapter 41 - Glands and Hormones]
===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=endocrine endocrine] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=pineal_gland pineal gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=hypothalmus hypothalamus] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=pituitary_gland pituitary gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=thyroid_gland thyroid gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=parathyroid_gland parathyroid gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=thymus_gland thymus gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=endocrine_pancreas endocrine pancreas] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=adrenal_gland adrenal gland]
* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=endocrine_development endocrine development]

==Histology==
===Adult===
<gallery>
File:Pineal_histology_001.jpg|Pineal (high power)
File:Thyroid_histology_001.jpg|Thyroid (low power)
File:Thyroid_histology_002.jpg|Thyroid (high power)
File:Parathyroid_histology_001.jpg|Parathyroid (low power)
File:Parathyroid_histology_002.jpg|Parathyroid (high power)
File:Pituitary histology 001.jpg|Pituitary - adenohypophysis
File:Pituitary histology 002.jpg|Pituitary - adenohypophysis
File:Pituitary histology 003.jpg|Pituitary - neurohypophysis
File:Adrenal histology 001.jpg|Adrenal - Cortex and Medulla
File:Adrenal histology 002.jpg|Adrenal - Cortical Zones
File:Adrenal histology 003.jpg|Adrenal - Zona Reticularis and Medulla
File:Pancreatic islet.png|Pancreatic islet
</gallery>

===Embryonic===
<gallery>

File:Stage22_pancreas_b.jpg|Stage 22 - Pancreatic duct
File:Stage22 adrenal.jpg|Stage 22 - Adrenal gland
File:Week10 adrenal.jpg|Week 10 - Adrenal gland
</gallery>

==Terms==

'''adrenocorticotropin''' - (ACTH or corticotropin) anterior pituitary, peptide hormone

'''antidiuretic hormone''' - (ADH) hypothalamus, peptide hormone

'''atrial natriuretic factor''' - (ANP) heart, , peptide hormone

'''calcitonin''' - (CT) C cells of thyroid, peptide hormone

'''follicle stimulating hormone''' - (FSH) pituitary, protein hormone

'''growth hormone''' - (GH) pituitary, peptide hormone

'''human chorionic gonadotropin''' - (hCG) pancreas glycoprotein hormone with 2 subunits (alpha and beta joined non covalently). Similar in structure to luteinizing hormone (LH), hCG exists in multiple hormonal and non-endocrine agents (regular hCG, hyperglycosylated hCG and the free beta-subunit of hyperglycosylated hCG). [http://www.ncbi.nlm.nih.gov/pubmed/19171054 PMID: 19171054]

'''lutenizing hormone''' - (LH) pituitary, protein hormone

'''melaocyte stimulating hormone''' - (MSH) pituitary, peptide hormone

'''prolactin''' - (PRL) pituitary, peptide hormone

'''parathyroid hormone''' - (PTH) parathyroid, peptide hormone

'''thyroid hormone''' - (TH) thyroid,amino acid derivative

'''thyroid stimulating hormone''' - (TSH) pituitary, protein hormone

[[Category:Endocrine]] [[Category:Adrenal]] [[Category:Thyroid]] [[Category:Parathyroid]] [[Category:Pituitary]] [[Category:Pancreas]] [[Category:Genital]]

{{2012ANAT2341}}

Lecture - Endocrine Development

2013-10-07T03:50:24Z

Z3283213:

==Introduction==
[[File:Week10 adrenal.jpg|thumb|300px|Human adrenal gland ([[Second_Trimester|Week 10]])]]
The endocrine system resides within specific endocrine organs and both organs and tissues with other specific functions. Epithelia (ectoderm and endoderm) form the majority of the “ductless” endocrine glands like gastrointestinal and skin associated “ducted” glands. Differentiation of several also organs involves a epithelial/mesenchye interaction, seen in repeated in many differentiation of many different tissues. The endocrine glands produce hormones, which are distributed by the vascular system to the many body tissues, subsequently these organs are richly vascularized.

Hormones “orchestrate” responses in other tissues, including other endocrine organs, and these overall effects can be similar or different in different tissues. These signaling pathways are often described as "axes" the two major types are the: '''HPA''' ('''H'''ypothalamus-'''P'''ituitary-'''A'''drenal) and '''HPG''' ('''H'''ypothalamus-'''P'''ituitary-'''G'''onad). These hormone effects (like music) can be rapid, slow, brief, diurnal, or long-term. Hormone effects can be mimicked, stimulated, and blocked by therapeutic drugs, nutritional and environmental chemicals. Importantly, fetal endocrine development is required for normal fetal growth and differentiation.

{|

|}

{|
| [[File:Podcast icon.jpg]]
| --[[User:S8600021|Mark Hill]] 06:17, 26 September 2011 (EST) '''Interested in endocrine and hormone history?''' Listen to ABC Radio Ockham's Razor 2005-07-31 Centenary of the word "hormone" ([[File:Audio_-_centenary_of_hormone.mp3]]), by Sydney medical scientist (from SOMS) and writer Dr John Carmody commemorates the centenary of the entry of the word 'hormone' into the English language.
|}

==Lecture Objectives==
{|
| width="500px"|
* Understanding of hormone types
* Understanding of endocrine gland development
* Understanding of endocrine developmental functions

Lecture Date: 2013-10-08 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Endocrine Development.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

| [[File:Historic-pituitary.jpg|200px]]

Historic drawing of the Pituitary.
|}

==Textbooks==
The endocrine "System" is not covered by a specific chapter in the embryology textbooks and you will need to look for related chapters on the development of individual components (some selected examples are listed below). Use the listed Endocrinology textbook for detained descriptions of function.
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Endocrine Links}} | [[2010_Lecture_17|2010 Lecture]]
|}

===Endocrinology - An Integrated Approach===
{|
| [[File:Endocrinology - An Integrated Approach.png|80px]]
| Nussey, S. and Whitehead, S. (2001). ''Endocrinology - An Integrated Approach''. UK Oxford: BIOS Scientific Publishers. ISBN-10: 1-85996-252-1.

[[Talk:Lecture_-_Endocrine_Development#Endocrinology_-_An_Integrated_Approach|Detailed Table of Contents]] | [http://www.ncbi.nlm.nih.gov/books/NBK22 Bookshelf Link]

* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A3/ Chapter 1. Principles of endocrinology]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A43/ Chapter 2. The endocrine pancreas]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/ Chapter 3. The thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A442/ Chapter 4. The adrenal gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A742/ Chapter 5. The parathyroid glands and vitamin D]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A972/ Chapter 6. The gonad]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A1257/ Chapter 7. The pituitary gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A1527/ Chapter 8. Cardiovascular and renal endocrinology]
|}

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00009-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00009-6 Chapter 9 – Pharyngeal Apparatus, Face, and Neck]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00012-6 Chapter 12 - Urogenital System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10016-8 Chapter 16 - Development of the Pharyngeal Apparatus and Face]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10015-6 Chapter 15 - Development of the Urogenital System]
|}

:'''Links:''' [[Embryology Textbooks]]

==Hormones==
[[File:Steroid hormone receptor signaling.jpg|thumb|Steroid hormone receptor signaling<ref><pubmed>17464358</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1853070 PMC1853070] | [http://www.nursa.org/article.cfm?doi=10.1621/nrs.05003 Nucl Recept Signal.]</ref>]]
===Hormone Types===
[[File:Steroid biosynthesis pathway.png|thumb|Steroid biosynthesis pathway]]
* '''Amino acid derivatives''' - noradrenaline (norepinepherine), adrenalin (epinepherine) , thyroid hormone
* '''Proteins, peptides''' - thyroid stimulating hormone, leutenising hormone, follicle stimulating hormone
* '''Steroids''' - androgens, glucocorticoids, mineralocorticoids

===Hormone Actions===
All hormones act upon cells in different tissues and can be classified by the "distance" of their action, the classical description is that hormones are delivered by the blood.

* '''Autocrine''' - acts on self (extracellular fluid).
* '''Paracrine''' - acts locally (extracellular fluid or blood).
* '''Endocrine''' - acts by secretion into blood stream (endocrine organs are richly vascularized).

===Hormone Receptors===
A cell or tissue can only directly respond to a hormone if it expresses a receptor for that hormone.

Hormone receptors are either:
# '''cell surface''' - modified amino acids, peptides, proteins.
# '''intracellular cytoplasmic/nuclear''' - steroids.

==Endocrine Origins==

* Derived from epithelia - covering embryo, lining gastrointestinal tract, lining coelomic cavity
* Also mesenchymal contribution

==Pineal Gland==
[[File:pineal-body.jpg|thumb|Adult pineal body]]
[[File:Pineal gland position.jpg|thumb|Pineal gland position]]

* part of epithalmus - neurons, glia and pinealocytes
* pinealocytes secrete melatonin - cyclic nature of activity, melatonin lowest during daylight
** inhibit hypothalamic secretion of GnRH until puberty, pineal gland then rapidly regresses.
* other activities - possibly gamete maturation, antioxidant effect, protect neurons?

===Pineal Development===
* Neuroectoderm - prosenecephalon then diencephalon
* caudal roof, median diverticulum, epiphysis
* Initially a hollow diverticulum, cell proliferation to solid, pinealocytes (neuroglia), cone-shaped gland innervated by epithalmus

:'''Links:''' [[Endocrine - Pineal Development]]
==Hypothalamus==

'''Hormones''' - Thyrotrophin releasing hormone (TRH), Corticotrophin releasing hormone (CRH), Arginine vasopressin (AVP), Gonadotrophin releasing hormone (GnRH), Growth hormone releasing hormone (GHRH), Somatostatin, Prolactin relasing factor (PRF), Dopamine

===Hypothalamus Development===
* Neuroectoderm - prosenecephalon then diencephalon
* ventro-lateral wall intermediate zone proliferation
* Mamillary bodies - form pea-sized swellings ventral wall of hypothalamus

:'''Links:''' [[Endocrine - Hypothalamus Development]]
==Pituitary==
[[File:Embryonic_and_fetal_pituitary.jpg]]
[[File:Historic-pituitary.jpg|thumb|Adult pituitary]]

'''Anterior pituitary hormones''' - Thyroid-stimulating hormone (TSH), Adrenocorticotrophic hormone (ACTH), Luteinizing hormone (LH), Follicle-stimulating hormone (FSH), Somatotrophin/growth hormone (GH), Prolactin (PRL), Melanocyte-stimulating hormone (MSH)

'''Posterior pituitary hormones''' - Oxytocin, Arginine vasopressin

===Pituitary Development===
[[File:Pituitary rabbit development.jpg|thumb|Pituitary rabbit development]]
{|
| [[File:Pituitary development animation.gif]]
| '''Blue''' - neural tube ectoderm

'''Red''' - surface ectoderm
|}

* Dual ectoderm origins
** Ectoderm - ectoderm roof of stomodeum, Rathke's pouch, adenohypophysis
** Neuroectoderm - prosenecephalon then diencephalon, neurohypophysis

'''Adenohypophysis'''
* Anterior wall proliferates - pars distalis
* Posterior wall little growth – pars intermedia
* Rostral growth around infundibular stem – pars tuberalis

'''Neurohypophysis'''
* Infundibulum – median eminence, infundibulum, pars nervosa

===Pituitary Timeline===
* '''Week 4''' - hypophysial pouch, Rathke’s pouch, diverticulum from roof
* '''Week 5''' - elongation, contacts infundibulum, diverticulum of diencephalon
* '''Week 6''' - connecting stalk between pouch and oral cavity degenerates
* '''Week 8''' - basophilic staining cells appear
* '''Week 9''' - acidophilic staining cells appear
* '''Week 10''' - growth hormone and ACTH detectable
* '''Week 16''' - adenohypophysis fully differentiated and TSH increases to peak at 22 weeks
* '''Week 20 to 24''' - growth hormone levels peak, then decline
* '''Birth''' - second TSH surge and decreases postnatally

:'''Links:''' [[Endocrine - Pituitary Development]] | [http://www.med.unc.edu/embryo_images/unit-nervous/nerv_htms/nerv016.htm Embryo Images - Pituitary] | [[Talk:Lecture - Endocrine Development#Chapter_7._The_pituitary_gland|Endocrinology]]

==Thyroid==
[[File:Stage13 and 22 thyroid development a.jpg|thumb|Stage 13 and Stage 22 thyroid development]]
* Functions from week 10, required for neural development, stimulates metabolism (protein, carbohydrate, lipid), reduced/absence = cretinism (see abnormalities)

'''Hormones''' - (amino acid derivatives) Thyroxine (T4), Triiodothyronine (T3)

===Thyroid Development===
{|
|
* thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* tongue grows, cells descend in neck
* thyroglossal duct - proximal end at the foramen cecum of tongue thyroglossal duct
* thyroid diverticulum - hollow then solid, right and left lobes, central isthmus
| [[File:Tongue1.png|thumb|foramen caecum]]
| [[File:Thyroid-development-cartoon.jpg|thumb|Thyroid development cartoon]]
|}
===Thyroid Timeline===
* 24 days - thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* Week 11 - colloid appearance in thyroid follicles, iodine and thyroid hormone (TH) synthesis
growth factors (insulin-like, epidermal) stimulates follicular growth

===Fetal Thyroid Hormone===
* Initial secreted biologically inactivated by modification, late fetal secretion develops brown fat
* Iodine deficiency- during this period, leads to neurological defects (cretinism)
* Birth - TSH levels increase, thyroxine (T3) and T4 levels increase to 24 h, then 5-7 days postnatal decline to normal levels

:'''Links:''' [[Endocrine - Thyroid Development]] | [[Abnormal_Development_-_Iodine_Deficiency|Iodine Deficiency]] | [[Talk:Lecture - Endocrine Development#Chapter_3._The_thyroid_gland|Endocrinology]]

==Parathyroid==
[[File:Parathyroid adult.jpg|thumb|Parathyroid adult]]

* Parathyroid Hormone - Increase calcium ions [Ca2+], stimulates osteoclasts, increase Ca GIT absorption (opposite effect to calcitonin)
* Adult Calcium and Phosphate - Daily turnover in human with dietary intake of 1000 mg/day
* secreted by chief cells
Principal cells cords of cells
===Parathyroid Development===
[[File:Pharyngeal pouches.jpg|thumb|Pharyngeal pouches]]
* Endoderm - third and fourth pharyngeal pouches, could also have ectoderm and neural crest
** 3rd Pharyngeal Pouch - inferior parathyroid, initially descends with thymus
** 4th Pharyngeal Pouch - superior parathyroid
* Week 6 - diverticulum elongate, hollow then solid, dorsal cell proliferation
* Fetal parathyroids - respond to calcium levels, fetal calcium levels higher than maternal

:'''Links:''' [[Endocrine - Parathyroid Development]]
==Thymus==

* Thymus - bone-marrow lymphocyte precursors become thymocytes, and subsequently mature into T lymphocytes (T cells)
* Thymus hormones - thymosins stimulate the development and differentiation of T lymphocytes

===Thymus Development===

* Endoderm - third pharyngeal pouch
* Week 6 - diverticulum elongates, hollow then solid, ventral cell proliferation
* Thymic primordia - surrounded by neural crest mesenchyme, epithelia/mesenchyme interaction

:'''Links:''' [[Endocrine - Thymus Development]]
==Pancreas==
[[File:Pancreas adult.jpg|thumb|Pancreas adult]]
[[File:Pancreas cartoon.jpg|thumb|pancreas structure]]

* Functions - exocrine (amylase, alpha-fetoprotein), 99% by volume; endocrine (pancreatic islets) 1% by volume
* Exocrine function - begins after birth
* Endocrine function - from 10 to 15 weeks onward hormone release
** exact roles of hormones in regulating fetal growth?

===Pancreas Development===
[[File:Pancreatic_duct_developing.jpg|thumb|Pancreatic buds and duct developing]]
[[File:Stage22_pancreas_a.jpg|thumb|Stage22 pancreas]]
* Pancreatic buds - duodenal level endoderm, splanchnic mesoderm forms dorsal and ventral mesentery, dorsal bud (larger, first), ventral bud (smaller, later)
* Pancreas Endoderm - pancreas may be opposite of liver
** Heart cells promote/notochord prevents liver formation
** Notochord may promote pancreas formation
** Heart may block pancreas formation

* Duodenum growth/rotation - brings ventral and dorsal buds together, fusion of buds
* Pancreatic duct - ventral bud duct and distal part of dorsal bud, exocrine function
* Islet cells - cords of endodermal cells form ducts, from which cells bud off to form islets

===Pancreatic Islets===
* Islets of Langerhans - 4 endocrine cell types
* '''Alpha''' - glucagon, mobilizes lipid
* '''Beta''' - insulin, increase glucose uptake
** Beta cells, stimulate fetal growth, continue to proliferate to postnatal, in infancy most abundant
* '''Delta''' - somatostatin, inhibits glucagon, insulin secretion
* '''F-cells''' - pancreatic polypeptide

===Pancreas Timeline===
* Week 7 to 20 - pancreatic hormones secretion increases, small amount maternal insulin
* Week 10 - glucagon (alpha) differentiate first, somatostatin (delta), insulin (beta) cells differentiate, insulin secretion begins
* Week 15 - glucagon detectable in fetal plasma

:'''Links:''' [[Endocrine - Pancreas Development]] | [[Gastrointestinal Tract - Pancreas Development]]
==Adrenal==

* Richly vascularized - arterioles passing through cortex, capillaries from cortex to medulla, portal-like circulation
* Fetal Cortex - produces a steroid precursor (DEA), converted by placenta into estrogen
* Adult Medulla - produces adrenalin (epinephrine), noradrenaline (norepinephrine)
* Fetal adrenal hormones - influence lung maturation

'''Adrenal cortical hormones''' - (steroids) Cortisol, Aldosterone, Dehydroepiandrosterone
* zona glomerulosa - regulated by renin-angiotensin-aldosterone system controlled by the juxtaglomerular apparatus of the kidney.
* zona fasciculata - regulated by hypothalamo-pituitary axis with the release of CRH and ACTH respectively.

'''Adrenal medullary hormones''' - (amino acid derivatives) Epinephrine, Norepinephrine

===Adrenal Development===
[[File:Week10 adrenal.jpg|thumb|Week 10 adrenal gland]]
{|
|
* Fetal Adrenals - fetal cortex later replaced by adult cortex
* Week 6 - fetal cortex, from mesothelium adjacent to dorsal mesentery; Medulla, neural crest cells from adjacent sympathetic ganglia
* Adult cortex - mesothelium mesenchyme encloses fetal cortex

'''Adrenal Cortex'''
* mesothelium origin, epithelium lining the body cavity at the site of adrenal development
* Late Fetal Period - differentiates to form cortical zones
* Birth - zona glomerulosa, zona fasiculata present
* Year 3 - zona reticularis present

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A442&rendertype=box&id=A466 Endocrinology - Adrenal Cortex Development]

'''Adrenal Medulla'''
* neural crest origin, migrate adjacent to coelomic cavity, initially uncapsulated and not surrounded by fetal cortex, cells have neuron-like morphology
* 2 cell types - secrete epinepherine (adrenaline) 80%; secrete norepinepherine (noradrenaline* 20%

| {{Adrenal movie}}
|}

:'''Links:''' [[Endocrine - Adrenal Development]]

==Gonad==
[[File:XXhpgaxis.gif|thumb|Female HPG axis]]

HPG Axis - [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A972&rendertype=box&id=A1057 Endocrinology - Simplified diagram of the actions of gonadotrophins]

===Gonad Development===
--[[User:S8600021|Mark Hill]] 07:31, 27 September 2011 (EST) Covered in last weeks [[Lecture_-_Genital_Development|lecture]] and [[2011_Lab_8|lab]].

* mesoderm - mesothelium and underlying mesenchyme, primordial germ cells
* Gonadal ridge - mesothelium thickening, medial mesonephros
* Primordial Germ cells - yolk sac, to mesentery of hindgut, to genital ridge of developing kidney

'''Differentiation'''
* testis-determining factor (TDF) from Y chromosome: presence (testes), absence (ovaries)

'''Testis'''
* 8 Weeks, mesenchyme, interstitial cells (of Leydig) secrete testosterone, androstenedione
* 8 to 12 Weeks - hCG stimulates testosterone production
* Sustentacular cells - produce anti-mullerian hormone to puberty

'''Ovary'''
* X chromosome genes regulate ovary development

:'''Links:''' [[Endocrine - Gonad Development]]

==Placenta==
[[File:Trophoblast hCG function.jpg|thumb|Trophoblast hCG function]]
* Human chorionic gonadotrophin (hCG) - like leutenizing hormone, supports corpus luteum in ovary, pregnant state rather than menstrual, maternal urine in some pregnancy testing

* Human chorionic somatommotropin (hCS) - or placental lactogen stimulate (maternal) mammary development
* Human chorionic thyrotropin (hCT)
* Human chorionic corticotropin (hCACTH)
* progesterone and estrogens - support maternal endometrium
* Relaxin

* Placenta - Maternal (decidua) and Fetal (trophoblastic cells, extraembryonic mesoderm) components
* Endocrine function - maternal and fetal precursors, synthesis and secretion
** Protein Hormones - chorionic gonadotropin (hCG), chorionic somatomammotropin (hCS) or placental lactogen (hPL), chorionic thyrotropin (hCT), chorionic corticotropin (hCACTH)
*** hCG - up to 20 weeks, fetal adrenal cortex growth and maintenance
*** hCS – rise through pregnancy, stimulates maternal metabolic processes, breast growth
** Steroid Hormones - progesterone (maintains pregnancy), estrogens (fetal adrenal/placenta)

:'''Links:''' [[Endocrine - Placenta Development]]
==Other Endocrine==
===Endocrine Heart===
* Atrial natriuretic peptide (ANP) - Increase Filtration rate / decrease Na+ reabsorption
* Endothelins - ET-1, ET-2, ET-3, Vasoconstriction / Increase NO
* Nitric oxide (NO) - Vasodilatation

===Endocrine Kidney===
* Renin - Increase Angiotensin-aldosterone system
* Prostaglandins - decrease Na+ reabsorption
* Erythropoietin - Increase Erythrocyte (rbc) production
* 1,25 (OH)2 vitamin D - calcium homeostasis
* Prekallikreins - Increase Kinin production

===GIT Endocrine===
Enteric control of digestive function
* Gastrin - Secreted from stomach (G cells), role in control of gastric acid secretion
* Cholecystokinin - small intestine hormone, stimulates secretion of pancreatic enzymes and bile
* Secretin - small intestine hormone (epithelial cells), stimulates secretion of bicarbonate-rich fluids from pancreas and liver

===Adipose Tissue===

* Leptin - polypeptide hormone produced in adipose and many other tissues with also many different roles
* Adiponectin - regulation of energy homeostasis and glucose and lipid metabolism, as well as acting as an anti-inflammatory on the cellular vascular wall
* Resistin - (for resistance to insulin, RETN) a 108 amino acid polypeptide and the related resistin-like protein-beta (Resistin-like molecule-beta, RELMbeta) stimulate endogenous glucose production

:'''Links:''' [[Endocrine - Other Tissues]]
==Endocrine Functional Changes==
* Puberty- Increased activity
* Menopause- Decreased activity
* Disease (diabetes, thyroid, kidney) suggested trends that genetics, health, nutrition, lifestyle may influence time that these events occur
* Pharmaceutical impact - birth control, steroids, Hormone Replacement Therapy (HRT)

==Abnormalities==
'''NIH Genes & Disease''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 Chapter 41 - Glands and Hormones]
===Pineal===
* hypoplasia - associated with retinal disease.
* tumours - in children are associated with abnormal puberty development.

===Pituitary===
* craniopharyngeal canal - Rathke's pouch abnormality, from the anterior part of the fossa hypophyseos of the sphenoid bone to the under surface of the skull.
* pituitary tumours (adenomas) - several abnormalities associated with abnormal levels of the hormonal output of the pituitary.
** Growth hormone (GH) adenomas - benign pituitary tumors lead to chronic high GH output levels, that may lead to acromegaly.
* Cushing's disease - caused either by a pituitary adenoma produces excess adrenocorticotropic hormone (ACTH, corticotropin) or due to ectopic tumors secreting ACTH or corticotropin-releasing hormone (CRH).

=== Thyroid ===
[[File:Thyroid_pyramidal_lobe.jpg|thumb|Thyroid pyramidal lobe]]
[[File:Thyroid uptake scans .jpg|thumb|Thyroid uptake scans]]
* Pyramidal lobe - from isthmus (50% of people) attached to hyoid bone distal end of thryoglossal duct.
* Congenital hypothyroidism - approximately 1 in 3000 births, associated with neurological abnormalities.
* Lingual thyroid gland - failure of thyroid descent.
* Thyroglossal cyst - persistance of thyroglossal duct. [http://www.upstate.edu/cdb/grossanat/imgs/tgdfig2.jpg Image - thyroglossal duct]
* Thyroglossal fistula - partial degeneration of the thyroglossal duct.
* Abnormal development of the thyroid - incomplete or excessive descent.
* Childhood hypothyroidism delays ossification and bone mineralization.

Iodine Deficiency
* A teaspoon of iodine, total lifetime requirement, cannot be stored for long periods by our body, tiny amounts are needed regularly
* Areas of endemic iodine deficiency, where soil and therefore crops and grazing animals do not provide sufficient dietary iodine to the populace
* food fortification and supplementation - Iodized salt programs and iodized oil supplements are the most common tools in fight against IDD

===Parathyroid===
* Usually four glands are present (2 on each side), but three to six glands have been found in human.
* Lower parathyroid glands arise from the third pharyngeal pouch and descend with the thymus. Variable descent can lead to a range of adult locations, from just beneath the mandible to the anterior mediastinum.

===Pancreas===
* Type 1 Diabetes - juvenile onset diabetes, more severe form of illness, increases risk of blindness, heart disease, kidney failure, neurological disease, T-lymphocyte-dependent autoimmune disease, infiltration and destruction of the islets of Langerhans, Approx 16 million Americans
* Type 2 Diabetes - loosely defined as "adult onset" diabetes, becoming more common cases of type 2 diabetes seen in younger people
* Risk of developing diabetes - environmental factors (food intake and exercise play an important role, either overweight or obese), Inherited factors (genes involved remain poorly defined)

===Adrenal===
* Congenital Adrenal Hyperplasia (CAH) - family of inherited disorders of adrenal steroidogenesis enzymes which impairs cortisol production by the adrenal cortex. Androgen excess leads newborn females with external genital ambiguity and postnatal progressive virilization in both sexes.
** Enzymes most commonly affected: 21-hydroxylase (21-OH), 11beta-hydroxylase, 3beta-hydroxysteroid dehydrogenase.
** Enzymes less commonly affected: 17alpha-hydroxylase/17,20-lyase and cholesterol desmolase.

* Pheochromocytomas (PCC) - Catecholamine-producing (neuro)endocrine tumor located in the adrenal medulla. Similar catecholamine-producing tumors outside the adrenal gland are called paragangliomas (PGL).

===Endocrine Disruptors===
Exogenous chemicals that interfere with the function of hormones. There are 3 main mechanisms: mimic, block or interfere.

'''Mimic''' - effects of natural hormones by binding receptors
* Diethylstilbestrol - (DES or diethylstilbetrol) a drug prescribed to women from 1938-1971 to prevent miscarriage in high-risk pregnancies. Acts as a potent estrogen (mimics natural hormone) and therefore a potential endocrine disruptor. Female fetus, increased risk abnormal reproductive tract and cancer. Male fetus, abnormal genitalia. Banned by USA FDA in 1979 as a teratogen, previously used as livestock growth promoter.

'''Block''' - binding of a hormone to receptor or hormone synthesis
* Finasteride - chemical used to prevent male pattern baldness and enlargement of prostate glands. An anti-androgen (blocks synthesis of dihydrotestosterone) and therefore a potential endocrine disruptor, exposed pregnant women can impact on male fetus genetial development.
* Vinclozolin - a dicarboximide fungicide, perinatal exposure in rats inhibits morphological sex differentiation. In adult rats, shown to cause gonad tumours (Leydig cell) and atrophy. Chemical has androgen-antagonist (antiandrogenic) activity, metabolies compete with natural androgen

'''Interfere''' - with hormone transport or elimination

* Polychlorinated biphenyl pollutants - (PCBs) Rats exposed to PCBs have low levels of thyroid hormone. Compete for binding sites of thyroid hormone transport protein. Without being bound to this protein, thyroid hormones are excreted from the body (McKinney et al. 1985; Morse et al. 1996)

==References==
<references/>

* Endocrinology: An Integrated Approach Nussey, S.S. and Whitehead, S.A. London:Taylor & Francis; c2001 [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A3&rendertype=box&id=A11 Major hormone types]
* Genes and Disease, Bethesda (MD): National Library of Medicine (US), NCBI [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 Chapter 41 - Glands and Hormones]
===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=endocrine endocrine] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=pineal_gland pineal gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=hypothalmus hypothalamus] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=pituitary_gland pituitary gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=thyroid_gland thyroid gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=parathyroid_gland parathyroid gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=thymus_gland thymus gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=endocrine_pancreas endocrine pancreas] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=adrenal_gland adrenal gland]
* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=endocrine_development endocrine development]

==Histology==
===Adult===
<gallery>
File:Pineal_histology_001.jpg|Pineal (high power)
File:Thyroid_histology_001.jpg|Thyroid (low power)
File:Thyroid_histology_002.jpg|Thyroid (high power)
File:Parathyroid_histology_001.jpg|Parathyroid (low power)
File:Parathyroid_histology_002.jpg|Parathyroid (high power)
File:Pituitary histology 001.jpg|Pituitary - adenohypophysis
File:Pituitary histology 002.jpg|Pituitary - adenohypophysis
File:Pituitary histology 003.jpg|Pituitary - neurohypophysis
File:Adrenal histology 001.jpg|Adrenal - Cortex and Medulla
File:Adrenal histology 002.jpg|Adrenal - Cortical Zones
File:Adrenal histology 003.jpg|Adrenal - Zona Reticularis and Medulla
File:Pancreatic islet.png|Pancreatic islet
</gallery>

===Embryonic===
<gallery>

File:Stage22_pancreas_b.jpg|Stage 22 - Pancreatic duct
File:Stage22 adrenal.jpg|Stage 22 - Adrenal gland
File:Week10 adrenal.jpg|Week 10 - Adrenal gland
</gallery>

==Terms==

'''adrenocorticotropin''' - (ACTH or corticotropin) anterior pituitary, peptide hormone

'''antidiuretic hormone''' - (ADH) hypothalamus, peptide hormone

'''atrial natriuretic factor''' - (ANP) heart, , peptide hormone

'''calcitonin''' - (CT) C cells of thyroid, peptide hormone

'''follicle stimulating hormone''' - (FSH) pituitary, protein hormone

'''growth hormone''' - (GH) pituitary, peptide hormone

'''human chorionic gonadotropin''' - (hCG) pancreas glycoprotein hormone with 2 subunits (alpha and beta joined non covalently). Similar in structure to luteinizing hormone (LH), hCG exists in multiple hormonal and non-endocrine agents (regular hCG, hyperglycosylated hCG and the free beta-subunit of hyperglycosylated hCG). [http://www.ncbi.nlm.nih.gov/pubmed/19171054 PMID: 19171054]

'''lutenizing hormone''' - (LH) pituitary, protein hormone

'''melaocyte stimulating hormone''' - (MSH) pituitary, peptide hormone

'''prolactin''' - (PRL) pituitary, peptide hormone

'''parathyroid hormone''' - (PTH) parathyroid, peptide hormone

'''thyroid hormone''' - (TH) thyroid,amino acid derivative

'''thyroid stimulating hormone''' - (TSH) pituitary, protein hormone

[[Category:Endocrine]] [[Category:Adrenal]] [[Category:Thyroid]] [[Category:Parathyroid]] [[Category:Pituitary]] [[Category:Pancreas]] [[Category:Genital]]

{{2012ANAT2341}}

Lecture - Endocrine Development

2013-10-07T03:48:47Z

Z3283213:

==Introduction==
[[File:Week10 adrenal.jpg|thumb|300px|Human adrenal gland ([[Second_Trimester|Week 10]])]]
The endocrine system resides within specific endocrine organs and both organs and tissues with other specific functions. Epithelia (ectoderm and endoderm) form the majority of the “ductless” endocrine glands like gastrointestinal and skin associated “ducted” glands. Differentiation of several also organs involves a epithelial/mesenchye interaction, seen in repeated in many differentiation of many different tissues. The endocrine glands produce hormones, which are distributed by the vascular system to the many body tissues, subsequently these organs are richly vascularized.

Hormones “orchestrate” responses in other tissues, including other endocrine organs, and these overall effects can be similar or different in different tissues. These signaling pathways are often described as "axes" the two major types are the: '''HPA''' ('''H'''ypothalamus-'''P'''ituitary-'''A'''drenal) and '''HPG''' ('''H'''ypothalamus-'''P'''ituitary-'''G'''onad). These hormone effects (like music) can be rapid, slow, brief, diurnal, or long-term. Hormone effects can be mimicked, stimulated, and blocked by therapeutic drugs, nutritional and environmental chemicals. Importantly, fetal endocrine development is required for normal fetal growth and differentiation.

{|
Lecture Date: 2013-10-08 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Endocrine Development.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

|}

{|
| [[File:Podcast icon.jpg]]
| --[[User:S8600021|Mark Hill]] 06:17, 26 September 2011 (EST) '''Interested in endocrine and hormone history?''' Listen to ABC Radio Ockham's Razor 2005-07-31 Centenary of the word "hormone" ([[File:Audio_-_centenary_of_hormone.mp3]]), by Sydney medical scientist (from SOMS) and writer Dr John Carmody commemorates the centenary of the entry of the word 'hormone' into the English language.
|}

==Lecture Objectives==
{|
| width="500px"|
* Understanding of hormone types
* Understanding of endocrine gland development
* Understanding of endocrine developmental functions

| [[File:Historic-pituitary.jpg|200px]]

Historic drawing of the Pituitary.
|}

==Textbooks==
The endocrine "System" is not covered by a specific chapter in the embryology textbooks and you will need to look for related chapters on the development of individual components (some selected examples are listed below). Use the listed Endocrinology textbook for detained descriptions of function.
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Endocrine Links}} | [[2010_Lecture_17|2010 Lecture]]
|}

===Endocrinology - An Integrated Approach===
{|
| [[File:Endocrinology - An Integrated Approach.png|80px]]
| Nussey, S. and Whitehead, S. (2001). ''Endocrinology - An Integrated Approach''. UK Oxford: BIOS Scientific Publishers. ISBN-10: 1-85996-252-1.

[[Talk:Lecture_-_Endocrine_Development#Endocrinology_-_An_Integrated_Approach|Detailed Table of Contents]] | [http://www.ncbi.nlm.nih.gov/books/NBK22 Bookshelf Link]

* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A3/ Chapter 1. Principles of endocrinology]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A43/ Chapter 2. The endocrine pancreas]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A235/ Chapter 3. The thyroid gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A442/ Chapter 4. The adrenal gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A742/ Chapter 5. The parathyroid glands and vitamin D]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A972/ Chapter 6. The gonad]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A1257/ Chapter 7. The pituitary gland]
* [http://www.ncbi.nlm.nih.gov/books/n/endocrin/A1527/ Chapter 8. Cardiovascular and renal endocrinology]
|}

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00009-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00009-6 Chapter 9 – Pharyngeal Apparatus, Face, and Neck]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00012-6 Chapter 12 - Urogenital System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10016-8 Chapter 16 - Development of the Pharyngeal Apparatus and Face]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10015-6 Chapter 15 - Development of the Urogenital System]
|}

:'''Links:''' [[Embryology Textbooks]]

==Hormones==
[[File:Steroid hormone receptor signaling.jpg|thumb|Steroid hormone receptor signaling<ref><pubmed>17464358</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1853070 PMC1853070] | [http://www.nursa.org/article.cfm?doi=10.1621/nrs.05003 Nucl Recept Signal.]</ref>]]
===Hormone Types===
[[File:Steroid biosynthesis pathway.png|thumb|Steroid biosynthesis pathway]]
* '''Amino acid derivatives''' - noradrenaline (norepinepherine), adrenalin (epinepherine) , thyroid hormone
* '''Proteins, peptides''' - thyroid stimulating hormone, leutenising hormone, follicle stimulating hormone
* '''Steroids''' - androgens, glucocorticoids, mineralocorticoids

===Hormone Actions===
All hormones act upon cells in different tissues and can be classified by the "distance" of their action, the classical description is that hormones are delivered by the blood.

* '''Autocrine''' - acts on self (extracellular fluid).
* '''Paracrine''' - acts locally (extracellular fluid or blood).
* '''Endocrine''' - acts by secretion into blood stream (endocrine organs are richly vascularized).

===Hormone Receptors===
A cell or tissue can only directly respond to a hormone if it expresses a receptor for that hormone.

Hormone receptors are either:
# '''cell surface''' - modified amino acids, peptides, proteins.
# '''intracellular cytoplasmic/nuclear''' - steroids.

==Endocrine Origins==

* Derived from epithelia - covering embryo, lining gastrointestinal tract, lining coelomic cavity
* Also mesenchymal contribution

==Pineal Gland==
[[File:pineal-body.jpg|thumb|Adult pineal body]]
[[File:Pineal gland position.jpg|thumb|Pineal gland position]]

* part of epithalmus - neurons, glia and pinealocytes
* pinealocytes secrete melatonin - cyclic nature of activity, melatonin lowest during daylight
** inhibit hypothalamic secretion of GnRH until puberty, pineal gland then rapidly regresses.
* other activities - possibly gamete maturation, antioxidant effect, protect neurons?

===Pineal Development===
* Neuroectoderm - prosenecephalon then diencephalon
* caudal roof, median diverticulum, epiphysis
* Initially a hollow diverticulum, cell proliferation to solid, pinealocytes (neuroglia), cone-shaped gland innervated by epithalmus

:'''Links:''' [[Endocrine - Pineal Development]]
==Hypothalamus==

'''Hormones''' - Thyrotrophin releasing hormone (TRH), Corticotrophin releasing hormone (CRH), Arginine vasopressin (AVP), Gonadotrophin releasing hormone (GnRH), Growth hormone releasing hormone (GHRH), Somatostatin, Prolactin relasing factor (PRF), Dopamine

===Hypothalamus Development===
* Neuroectoderm - prosenecephalon then diencephalon
* ventro-lateral wall intermediate zone proliferation
* Mamillary bodies - form pea-sized swellings ventral wall of hypothalamus

:'''Links:''' [[Endocrine - Hypothalamus Development]]
==Pituitary==
[[File:Embryonic_and_fetal_pituitary.jpg]]
[[File:Historic-pituitary.jpg|thumb|Adult pituitary]]

'''Anterior pituitary hormones''' - Thyroid-stimulating hormone (TSH), Adrenocorticotrophic hormone (ACTH), Luteinizing hormone (LH), Follicle-stimulating hormone (FSH), Somatotrophin/growth hormone (GH), Prolactin (PRL), Melanocyte-stimulating hormone (MSH)

'''Posterior pituitary hormones''' - Oxytocin, Arginine vasopressin

===Pituitary Development===
[[File:Pituitary rabbit development.jpg|thumb|Pituitary rabbit development]]
{|
| [[File:Pituitary development animation.gif]]
| '''Blue''' - neural tube ectoderm

'''Red''' - surface ectoderm
|}

* Dual ectoderm origins
** Ectoderm - ectoderm roof of stomodeum, Rathke's pouch, adenohypophysis
** Neuroectoderm - prosenecephalon then diencephalon, neurohypophysis

'''Adenohypophysis'''
* Anterior wall proliferates - pars distalis
* Posterior wall little growth – pars intermedia
* Rostral growth around infundibular stem – pars tuberalis

'''Neurohypophysis'''
* Infundibulum – median eminence, infundibulum, pars nervosa

===Pituitary Timeline===
* '''Week 4''' - hypophysial pouch, Rathke’s pouch, diverticulum from roof
* '''Week 5''' - elongation, contacts infundibulum, diverticulum of diencephalon
* '''Week 6''' - connecting stalk between pouch and oral cavity degenerates
* '''Week 8''' - basophilic staining cells appear
* '''Week 9''' - acidophilic staining cells appear
* '''Week 10''' - growth hormone and ACTH detectable
* '''Week 16''' - adenohypophysis fully differentiated and TSH increases to peak at 22 weeks
* '''Week 20 to 24''' - growth hormone levels peak, then decline
* '''Birth''' - second TSH surge and decreases postnatally

:'''Links:''' [[Endocrine - Pituitary Development]] | [http://www.med.unc.edu/embryo_images/unit-nervous/nerv_htms/nerv016.htm Embryo Images - Pituitary] | [[Talk:Lecture - Endocrine Development#Chapter_7._The_pituitary_gland|Endocrinology]]

==Thyroid==
[[File:Stage13 and 22 thyroid development a.jpg|thumb|Stage 13 and Stage 22 thyroid development]]
* Functions from week 10, required for neural development, stimulates metabolism (protein, carbohydrate, lipid), reduced/absence = cretinism (see abnormalities)

'''Hormones''' - (amino acid derivatives) Thyroxine (T4), Triiodothyronine (T3)

===Thyroid Development===
{|
|
* thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* tongue grows, cells descend in neck
* thyroglossal duct - proximal end at the foramen cecum of tongue thyroglossal duct
* thyroid diverticulum - hollow then solid, right and left lobes, central isthmus
| [[File:Tongue1.png|thumb|foramen caecum]]
| [[File:Thyroid-development-cartoon.jpg|thumb|Thyroid development cartoon]]
|}
===Thyroid Timeline===
* 24 days - thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum
* Week 11 - colloid appearance in thyroid follicles, iodine and thyroid hormone (TH) synthesis
growth factors (insulin-like, epidermal) stimulates follicular growth

===Fetal Thyroid Hormone===
* Initial secreted biologically inactivated by modification, late fetal secretion develops brown fat
* Iodine deficiency- during this period, leads to neurological defects (cretinism)
* Birth - TSH levels increase, thyroxine (T3) and T4 levels increase to 24 h, then 5-7 days postnatal decline to normal levels

:'''Links:''' [[Endocrine - Thyroid Development]] | [[Abnormal_Development_-_Iodine_Deficiency|Iodine Deficiency]] | [[Talk:Lecture - Endocrine Development#Chapter_3._The_thyroid_gland|Endocrinology]]

==Parathyroid==
[[File:Parathyroid adult.jpg|thumb|Parathyroid adult]]

* Parathyroid Hormone - Increase calcium ions [Ca2+], stimulates osteoclasts, increase Ca GIT absorption (opposite effect to calcitonin)
* Adult Calcium and Phosphate - Daily turnover in human with dietary intake of 1000 mg/day
* secreted by chief cells
Principal cells cords of cells
===Parathyroid Development===
[[File:Pharyngeal pouches.jpg|thumb|Pharyngeal pouches]]
* Endoderm - third and fourth pharyngeal pouches, could also have ectoderm and neural crest
** 3rd Pharyngeal Pouch - inferior parathyroid, initially descends with thymus
** 4th Pharyngeal Pouch - superior parathyroid
* Week 6 - diverticulum elongate, hollow then solid, dorsal cell proliferation
* Fetal parathyroids - respond to calcium levels, fetal calcium levels higher than maternal

:'''Links:''' [[Endocrine - Parathyroid Development]]
==Thymus==

* Thymus - bone-marrow lymphocyte precursors become thymocytes, and subsequently mature into T lymphocytes (T cells)
* Thymus hormones - thymosins stimulate the development and differentiation of T lymphocytes

===Thymus Development===

* Endoderm - third pharyngeal pouch
* Week 6 - diverticulum elongates, hollow then solid, ventral cell proliferation
* Thymic primordia - surrounded by neural crest mesenchyme, epithelia/mesenchyme interaction

:'''Links:''' [[Endocrine - Thymus Development]]
==Pancreas==
[[File:Pancreas adult.jpg|thumb|Pancreas adult]]
[[File:Pancreas cartoon.jpg|thumb|pancreas structure]]

* Functions - exocrine (amylase, alpha-fetoprotein), 99% by volume; endocrine (pancreatic islets) 1% by volume
* Exocrine function - begins after birth
* Endocrine function - from 10 to 15 weeks onward hormone release
** exact roles of hormones in regulating fetal growth?

===Pancreas Development===
[[File:Pancreatic_duct_developing.jpg|thumb|Pancreatic buds and duct developing]]
[[File:Stage22_pancreas_a.jpg|thumb|Stage22 pancreas]]
* Pancreatic buds - duodenal level endoderm, splanchnic mesoderm forms dorsal and ventral mesentery, dorsal bud (larger, first), ventral bud (smaller, later)
* Pancreas Endoderm - pancreas may be opposite of liver
** Heart cells promote/notochord prevents liver formation
** Notochord may promote pancreas formation
** Heart may block pancreas formation

* Duodenum growth/rotation - brings ventral and dorsal buds together, fusion of buds
* Pancreatic duct - ventral bud duct and distal part of dorsal bud, exocrine function
* Islet cells - cords of endodermal cells form ducts, from which cells bud off to form islets

===Pancreatic Islets===
* Islets of Langerhans - 4 endocrine cell types
* '''Alpha''' - glucagon, mobilizes lipid
* '''Beta''' - insulin, increase glucose uptake
** Beta cells, stimulate fetal growth, continue to proliferate to postnatal, in infancy most abundant
* '''Delta''' - somatostatin, inhibits glucagon, insulin secretion
* '''F-cells''' - pancreatic polypeptide

===Pancreas Timeline===
* Week 7 to 20 - pancreatic hormones secretion increases, small amount maternal insulin
* Week 10 - glucagon (alpha) differentiate first, somatostatin (delta), insulin (beta) cells differentiate, insulin secretion begins
* Week 15 - glucagon detectable in fetal plasma

:'''Links:''' [[Endocrine - Pancreas Development]] | [[Gastrointestinal Tract - Pancreas Development]]
==Adrenal==

* Richly vascularized - arterioles passing through cortex, capillaries from cortex to medulla, portal-like circulation
* Fetal Cortex - produces a steroid precursor (DEA), converted by placenta into estrogen
* Adult Medulla - produces adrenalin (epinephrine), noradrenaline (norepinephrine)
* Fetal adrenal hormones - influence lung maturation

'''Adrenal cortical hormones''' - (steroids) Cortisol, Aldosterone, Dehydroepiandrosterone
* zona glomerulosa - regulated by renin-angiotensin-aldosterone system controlled by the juxtaglomerular apparatus of the kidney.
* zona fasciculata - regulated by hypothalamo-pituitary axis with the release of CRH and ACTH respectively.

'''Adrenal medullary hormones''' - (amino acid derivatives) Epinephrine, Norepinephrine

===Adrenal Development===
[[File:Week10 adrenal.jpg|thumb|Week 10 adrenal gland]]
{|
|
* Fetal Adrenals - fetal cortex later replaced by adult cortex
* Week 6 - fetal cortex, from mesothelium adjacent to dorsal mesentery; Medulla, neural crest cells from adjacent sympathetic ganglia
* Adult cortex - mesothelium mesenchyme encloses fetal cortex

'''Adrenal Cortex'''
* mesothelium origin, epithelium lining the body cavity at the site of adrenal development
* Late Fetal Period - differentiates to form cortical zones
* Birth - zona glomerulosa, zona fasiculata present
* Year 3 - zona reticularis present

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A442&rendertype=box&id=A466 Endocrinology - Adrenal Cortex Development]

'''Adrenal Medulla'''
* neural crest origin, migrate adjacent to coelomic cavity, initially uncapsulated and not surrounded by fetal cortex, cells have neuron-like morphology
* 2 cell types - secrete epinepherine (adrenaline) 80%; secrete norepinepherine (noradrenaline* 20%

| {{Adrenal movie}}
|}

:'''Links:''' [[Endocrine - Adrenal Development]]

==Gonad==
[[File:XXhpgaxis.gif|thumb|Female HPG axis]]

HPG Axis - [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A972&rendertype=box&id=A1057 Endocrinology - Simplified diagram of the actions of gonadotrophins]

===Gonad Development===
--[[User:S8600021|Mark Hill]] 07:31, 27 September 2011 (EST) Covered in last weeks [[Lecture_-_Genital_Development|lecture]] and [[2011_Lab_8|lab]].

* mesoderm - mesothelium and underlying mesenchyme, primordial germ cells
* Gonadal ridge - mesothelium thickening, medial mesonephros
* Primordial Germ cells - yolk sac, to mesentery of hindgut, to genital ridge of developing kidney

'''Differentiation'''
* testis-determining factor (TDF) from Y chromosome: presence (testes), absence (ovaries)

'''Testis'''
* 8 Weeks, mesenchyme, interstitial cells (of Leydig) secrete testosterone, androstenedione
* 8 to 12 Weeks - hCG stimulates testosterone production
* Sustentacular cells - produce anti-mullerian hormone to puberty

'''Ovary'''
* X chromosome genes regulate ovary development

:'''Links:''' [[Endocrine - Gonad Development]]

==Placenta==
[[File:Trophoblast hCG function.jpg|thumb|Trophoblast hCG function]]
* Human chorionic gonadotrophin (hCG) - like leutenizing hormone, supports corpus luteum in ovary, pregnant state rather than menstrual, maternal urine in some pregnancy testing

* Human chorionic somatommotropin (hCS) - or placental lactogen stimulate (maternal) mammary development
* Human chorionic thyrotropin (hCT)
* Human chorionic corticotropin (hCACTH)
* progesterone and estrogens - support maternal endometrium
* Relaxin

* Placenta - Maternal (decidua) and Fetal (trophoblastic cells, extraembryonic mesoderm) components
* Endocrine function - maternal and fetal precursors, synthesis and secretion
** Protein Hormones - chorionic gonadotropin (hCG), chorionic somatomammotropin (hCS) or placental lactogen (hPL), chorionic thyrotropin (hCT), chorionic corticotropin (hCACTH)
*** hCG - up to 20 weeks, fetal adrenal cortex growth and maintenance
*** hCS – rise through pregnancy, stimulates maternal metabolic processes, breast growth
** Steroid Hormones - progesterone (maintains pregnancy), estrogens (fetal adrenal/placenta)

:'''Links:''' [[Endocrine - Placenta Development]]
==Other Endocrine==
===Endocrine Heart===
* Atrial natriuretic peptide (ANP) - Increase Filtration rate / decrease Na+ reabsorption
* Endothelins - ET-1, ET-2, ET-3, Vasoconstriction / Increase NO
* Nitric oxide (NO) - Vasodilatation

===Endocrine Kidney===
* Renin - Increase Angiotensin-aldosterone system
* Prostaglandins - decrease Na+ reabsorption
* Erythropoietin - Increase Erythrocyte (rbc) production
* 1,25 (OH)2 vitamin D - calcium homeostasis
* Prekallikreins - Increase Kinin production

===GIT Endocrine===
Enteric control of digestive function
* Gastrin - Secreted from stomach (G cells), role in control of gastric acid secretion
* Cholecystokinin - small intestine hormone, stimulates secretion of pancreatic enzymes and bile
* Secretin - small intestine hormone (epithelial cells), stimulates secretion of bicarbonate-rich fluids from pancreas and liver

===Adipose Tissue===

* Leptin - polypeptide hormone produced in adipose and many other tissues with also many different roles
* Adiponectin - regulation of energy homeostasis and glucose and lipid metabolism, as well as acting as an anti-inflammatory on the cellular vascular wall
* Resistin - (for resistance to insulin, RETN) a 108 amino acid polypeptide and the related resistin-like protein-beta (Resistin-like molecule-beta, RELMbeta) stimulate endogenous glucose production

:'''Links:''' [[Endocrine - Other Tissues]]
==Endocrine Functional Changes==
* Puberty- Increased activity
* Menopause- Decreased activity
* Disease (diabetes, thyroid, kidney) suggested trends that genetics, health, nutrition, lifestyle may influence time that these events occur
* Pharmaceutical impact - birth control, steroids, Hormone Replacement Therapy (HRT)

==Abnormalities==
'''NIH Genes & Disease''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 Chapter 41 - Glands and Hormones]
===Pineal===
* hypoplasia - associated with retinal disease.
* tumours - in children are associated with abnormal puberty development.

===Pituitary===
* craniopharyngeal canal - Rathke's pouch abnormality, from the anterior part of the fossa hypophyseos of the sphenoid bone to the under surface of the skull.
* pituitary tumours (adenomas) - several abnormalities associated with abnormal levels of the hormonal output of the pituitary.
** Growth hormone (GH) adenomas - benign pituitary tumors lead to chronic high GH output levels, that may lead to acromegaly.
* Cushing's disease - caused either by a pituitary adenoma produces excess adrenocorticotropic hormone (ACTH, corticotropin) or due to ectopic tumors secreting ACTH or corticotropin-releasing hormone (CRH).

=== Thyroid ===
[[File:Thyroid_pyramidal_lobe.jpg|thumb|Thyroid pyramidal lobe]]
[[File:Thyroid uptake scans .jpg|thumb|Thyroid uptake scans]]
* Pyramidal lobe - from isthmus (50% of people) attached to hyoid bone distal end of thryoglossal duct.
* Congenital hypothyroidism - approximately 1 in 3000 births, associated with neurological abnormalities.
* Lingual thyroid gland - failure of thyroid descent.
* Thyroglossal cyst - persistance of thyroglossal duct. [http://www.upstate.edu/cdb/grossanat/imgs/tgdfig2.jpg Image - thyroglossal duct]
* Thyroglossal fistula - partial degeneration of the thyroglossal duct.
* Abnormal development of the thyroid - incomplete or excessive descent.
* Childhood hypothyroidism delays ossification and bone mineralization.

Iodine Deficiency
* A teaspoon of iodine, total lifetime requirement, cannot be stored for long periods by our body, tiny amounts are needed regularly
* Areas of endemic iodine deficiency, where soil and therefore crops and grazing animals do not provide sufficient dietary iodine to the populace
* food fortification and supplementation - Iodized salt programs and iodized oil supplements are the most common tools in fight against IDD

===Parathyroid===
* Usually four glands are present (2 on each side), but three to six glands have been found in human.
* Lower parathyroid glands arise from the third pharyngeal pouch and descend with the thymus. Variable descent can lead to a range of adult locations, from just beneath the mandible to the anterior mediastinum.

===Pancreas===
* Type 1 Diabetes - juvenile onset diabetes, more severe form of illness, increases risk of blindness, heart disease, kidney failure, neurological disease, T-lymphocyte-dependent autoimmune disease, infiltration and destruction of the islets of Langerhans, Approx 16 million Americans
* Type 2 Diabetes - loosely defined as "adult onset" diabetes, becoming more common cases of type 2 diabetes seen in younger people
* Risk of developing diabetes - environmental factors (food intake and exercise play an important role, either overweight or obese), Inherited factors (genes involved remain poorly defined)

===Adrenal===
* Congenital Adrenal Hyperplasia (CAH) - family of inherited disorders of adrenal steroidogenesis enzymes which impairs cortisol production by the adrenal cortex. Androgen excess leads newborn females with external genital ambiguity and postnatal progressive virilization in both sexes.
** Enzymes most commonly affected: 21-hydroxylase (21-OH), 11beta-hydroxylase, 3beta-hydroxysteroid dehydrogenase.
** Enzymes less commonly affected: 17alpha-hydroxylase/17,20-lyase and cholesterol desmolase.

* Pheochromocytomas (PCC) - Catecholamine-producing (neuro)endocrine tumor located in the adrenal medulla. Similar catecholamine-producing tumors outside the adrenal gland are called paragangliomas (PGL).

===Endocrine Disruptors===
Exogenous chemicals that interfere with the function of hormones. There are 3 main mechanisms: mimic, block or interfere.

'''Mimic''' - effects of natural hormones by binding receptors
* Diethylstilbestrol - (DES or diethylstilbetrol) a drug prescribed to women from 1938-1971 to prevent miscarriage in high-risk pregnancies. Acts as a potent estrogen (mimics natural hormone) and therefore a potential endocrine disruptor. Female fetus, increased risk abnormal reproductive tract and cancer. Male fetus, abnormal genitalia. Banned by USA FDA in 1979 as a teratogen, previously used as livestock growth promoter.

'''Block''' - binding of a hormone to receptor or hormone synthesis
* Finasteride - chemical used to prevent male pattern baldness and enlargement of prostate glands. An anti-androgen (blocks synthesis of dihydrotestosterone) and therefore a potential endocrine disruptor, exposed pregnant women can impact on male fetus genetial development.
* Vinclozolin - a dicarboximide fungicide, perinatal exposure in rats inhibits morphological sex differentiation. In adult rats, shown to cause gonad tumours (Leydig cell) and atrophy. Chemical has androgen-antagonist (antiandrogenic) activity, metabolies compete with natural androgen

'''Interfere''' - with hormone transport or elimination

* Polychlorinated biphenyl pollutants - (PCBs) Rats exposed to PCBs have low levels of thyroid hormone. Compete for binding sites of thyroid hormone transport protein. Without being bound to this protein, thyroid hormones are excreted from the body (McKinney et al. 1985; Morse et al. 1996)

==References==
<references/>

* Endocrinology: An Integrated Approach Nussey, S.S. and Whitehead, S.A. London:Taylor & Francis; c2001 [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A3&rendertype=box&id=A11 Major hormone types]
* Genes and Disease, Bethesda (MD): National Library of Medicine (US), NCBI [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.chapter.41 Chapter 41 - Glands and Hormones]
===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=endocrine endocrine] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=pineal_gland pineal gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=hypothalmus hypothalamus] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=pituitary_gland pituitary gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=thyroid_gland thyroid gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=parathyroid_gland parathyroid gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=thymus_gland thymus gland] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=endocrine_pancreas endocrine pancreas] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=adrenal_gland adrenal gland]
* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=endocrine_development endocrine development]

==Histology==
===Adult===
<gallery>
File:Pineal_histology_001.jpg|Pineal (high power)
File:Thyroid_histology_001.jpg|Thyroid (low power)
File:Thyroid_histology_002.jpg|Thyroid (high power)
File:Parathyroid_histology_001.jpg|Parathyroid (low power)
File:Parathyroid_histology_002.jpg|Parathyroid (high power)
File:Pituitary histology 001.jpg|Pituitary - adenohypophysis
File:Pituitary histology 002.jpg|Pituitary - adenohypophysis
File:Pituitary histology 003.jpg|Pituitary - neurohypophysis
File:Adrenal histology 001.jpg|Adrenal - Cortex and Medulla
File:Adrenal histology 002.jpg|Adrenal - Cortical Zones
File:Adrenal histology 003.jpg|Adrenal - Zona Reticularis and Medulla
File:Pancreatic islet.png|Pancreatic islet
</gallery>

===Embryonic===
<gallery>

File:Stage22_pancreas_b.jpg|Stage 22 - Pancreatic duct
File:Stage22 adrenal.jpg|Stage 22 - Adrenal gland
File:Week10 adrenal.jpg|Week 10 - Adrenal gland
</gallery>

==Terms==

'''adrenocorticotropin''' - (ACTH or corticotropin) anterior pituitary, peptide hormone

'''antidiuretic hormone''' - (ADH) hypothalamus, peptide hormone

'''atrial natriuretic factor''' - (ANP) heart, , peptide hormone

'''calcitonin''' - (CT) C cells of thyroid, peptide hormone

'''follicle stimulating hormone''' - (FSH) pituitary, protein hormone

'''growth hormone''' - (GH) pituitary, peptide hormone

'''human chorionic gonadotropin''' - (hCG) pancreas glycoprotein hormone with 2 subunits (alpha and beta joined non covalently). Similar in structure to luteinizing hormone (LH), hCG exists in multiple hormonal and non-endocrine agents (regular hCG, hyperglycosylated hCG and the free beta-subunit of hyperglycosylated hCG). [http://www.ncbi.nlm.nih.gov/pubmed/19171054 PMID: 19171054]

'''lutenizing hormone''' - (LH) pituitary, protein hormone

'''melaocyte stimulating hormone''' - (MSH) pituitary, peptide hormone

'''prolactin''' - (PRL) pituitary, peptide hormone

'''parathyroid hormone''' - (PTH) parathyroid, peptide hormone

'''thyroid hormone''' - (TH) thyroid,amino acid derivative

'''thyroid stimulating hormone''' - (TSH) pituitary, protein hormone

[[Category:Endocrine]] [[Category:Adrenal]] [[Category:Thyroid]] [[Category:Parathyroid]] [[Category:Pituitary]] [[Category:Pancreas]] [[Category:Genital]]

{{2012ANAT2341}}

File:Genital Development.pdf

2013-09-23T07:43:22Z

Z3283213:

Lecture - Genital Development

2013-09-23T07:42:47Z

Z3283213:

== Introduction ==

[[File:Human idiogram.gif]] [[File:Historic-testis.jpg|240px]] [[File:Historic-ovary.jpg|240px]]

This section of notes covers genital development. Differences in development are dependent on a protein product of the Y chromosome SRY gene. Mesonephric duct (Wolffian Duct) and paramesonephric (Mullerian Duct) contribute the majority of male and female internal genital tract respectively.

Lecture Date: 2013-09-24 Lecture Time: 16:00 Venue: Biomedical Theatre E Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Genital Development.pdf‎‎| HERE]]

The audio will be available via the Echo system

|}

== Objectives ==
* Understand the development of the gonads in males and females
* Understand the chromosomal basis of sex determination
* Understand the differences in male/female internal duct develpoment.
* Understand the origins of the external genitalia
* Understand the developmental abnormalities in male and female development.

==Textbooks==
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Genital Links}} | [[2010_Lecture_16|2010 Lecture]]
|}
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00012-6 Chapter 12 - Urogenital System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10015-6 Chapter 15 - Development of the Urogenital System]
|}

:'''Links:''' [[Embryology Textbooks]] | [http://www.ncbi.nlm.nih.gov/pubmed/17237341 Review of mammalian sex determination]

==Movies==

{|
| {{Genital cartoons}}
| {{Gonad vascular movie}}
|}

== Objectives ==
* Understand the development of the gonads in males and females.
* Understand the chromosomal basis of sex determination.
* Understand the differences in male/female internal duct develpoment.
* Understand the origins of the external genitalia.
* Understand the developmental abnormalities in male and female development.

==Stages of Sexual Differentiation ==

# Development of the '''indifferent gonad''' - (genital ridge) early embryo
# Differentiation of gonad - ('''testis or ovary''') late embryo, defining event in sexual differentiation
# Differentiation of '''internal genital organs''' and ducts - late embryo to fetal
# Differentiation of '''external genitalia''' - fetal
# Development of '''secondary sexual characteristics''' - puberty

[[File:Stage22 mesonephros.jpg|thumb|Stage 22 mesonephros]]

[[File:Urogenital indifferent.jpg|240px|Urogenital Indifferent]] [[File:Urogenital male.jpg|240px|Urogenital Male]] [[File:Urogenital female.jpg|240px|Urogenital Female]]

==Human Timeline==
{|
|
* '''Week 3-4''' - primordial germ cells migrate during gastrulation
* '''Week 4''' - (24 days) intermediate mesoderm, pronephros primordium
* '''Week 5''' - (28 days) mesonephros and mesonephric duct
* '''Week 6''' - (35 days) ureteric bud, metanephros, genital ridge
* '''Week 7''' - (42 days) cloacal divison, gonadal primordium - indifferent to first appearance of testis cords
* '''Week 8''' - (49 days) paramesonephric duct, clear gonadal differentiation
* '''Week 9''' - (56 days) paramesonephric duct fusion (female)
* '''Week 15''' - (100 days) primary follicles (ovary)
| [[File:Amnion 001 icon.jpg|120px|link=Development Animation - Amniotic Cavity]]
|}

==1. Development of the indifferent gonad==
{|
|
* kidneys and genital ridge develop from '''intermediate mesoderm''', which lies between the lateral plate mesoderm and the somites.
* kidney develops in multiple stages, which occur in a rostrocaudal sequence; '''pronephros''' > '''mesonephros''' > '''metanephros''' (true adult kidney)
* earliest structure to form is the pronephros, in week 4, featuring a pronephric duct with associated nephrogenic mesenchyme.
* pronephros degenerates early on, leaving only the duct system running down to the cloaca – this becomes known as the '''mesonephric duct''' (Wolffian duct), in the embryo.
* next stage is the formation of the mesonephros, a series of mesonephric tubules in the mesenchyme that are induced by the mesonephric duct.
* mesonephros is a transient structure in mammals (In fish and amphibians it is the functioning adult kidney), but in mammals it serves mainly as the site for gonadal development.
| [[Image:Mesoderm cartoon4.gif]]
|}

[[File:Urogenital_sinus_001 icon.jpg|160px|link=Development_Animation_-_Urogenital_Sinus]] [[File:Adrenal_and_gonad_early_development.jpg|600px]]

Gonad and adrenal early development (not required to know molecular information)

==2. Differentiation of gonad into testis or ovary==
[[File:Human_Y_chromosome_SRY_region.jpg|thumb|Human Y chromosome - SRY region]]
===Chromosomal Sex Determination===

===Y chromosome ===
* [[Y Chromosome]] - 59 million base pairs, hypervariable in length, mostly non-functional repeats
* Current known protein-coding genes = 48 including ''SRY''
** ''SRY'' encodes a 204 amino acid protein (TDF) that is a member of the HMG (High mobility group) box class of DNA-binding proteins. Transcription factors bind to specific sites of DNA and regulates the transcription (expression) of other genes.

===X chromosome===

* [[X Chromosome]] - 155 million base pairs, contains about 5% of the haploid genome and encodes house-keeping and specialized functions.
* Genes such as Wnt-4 and DAX-1 necessary for initiation of female pathway ovary development
* An early discovery (1961) was that in order to have correct levels of X chromosome gene/protein expression (gene dosage), females must "inactivate" a single copy of the X chromosome in each and every cell. The initiator of the X inactivation process was discovered (1991) to be regulated by a region on the inactivating X chromosome encoding an '''X''' '''i'''nactive '''s'''pecific '''t'''ranscript (XIST), that acts as RNA and does not encode a protein.
* The genetic content of the X chromosome has been strongly conserved between species because these genes have become adapted to working as a single dose - Ohno's law
* X inactivation occurs randomly throughout the embryo, generating a mosaic of maternal and paternally derived X chromosome activity in all tissues and organs. This can be seen in the fur colour of tortoiseshell cats.

Overview - [http://www.ncbi.nlm.nih.gov/books/NBK26940/figure/A3716 MBoC - Figure 20-18. Influence of Sry on gonad development] | [http://www.ncbi.nlm.nih.gov/books/NBK26940/bin/ch20f18.jpg image] (image provides a good overview of the anatomy of sex determination, I will refer to this in the lecture and practical class)

===Supporting Cells===
* So called because they "support" the germ cells
'''Males'''
* develop as '''Sertoli cells'''
* SRY is expressed in the primordia of the supporting cells, transforming them into Sertoli cells that surround the germ cells and form testis cords
* SRY is not expressed in the other cell types of the gonad
** therefore the Sertoli cells instruct the germ cells and the steroid secreting cells to take the male path of development
* Embryonic Sertoli cells secrete anti-Mullerian hormone (AMH)
* Adult Sertoli cells line the inside of the seminiferous tubules and support spermatogenesis.
'''Females'''
* develop as Follicle cells ('''granulosa cells''')
* Follicle cells surround and nurture the developing oocytes
* In response to FSH, follicle cells proliferate
** After ovulation, these cells become luteal cells of the corpus luteum secreting progesterone and oestrogens

===Steroid secreting cell lineage===
'''Male'''
* Develop into '''Leydig cells''' (interstitial cells) which sit outside the seminiferous tubules
* Secrete testosterone in response to luteinizing hormone from the pituitary

'''Female'''
* Develop into '''theca cells''' that secrete androstenedione which can be converted by the follicle cells into estrogens

===Primordial Germ Cells===
[[File:Stage9_bf2-primordial_germ_cell_region.jpg|thumb|Primordial germ cell region (Stage 9)]]
[[File:Stage 13 image 086.jpg|thumb|Genital Ridge (Stage 13)]]
* Primordial germ cells (PGCs) are thought to be the first population of cells to migrate through the primitive streak in early gastrulation (week 3)
* cells then lie at the hindgut yolk sac junctional region
* later migrate into the genital ridge (germinal ridge) in early embryonic development.

{| border='0px'
|+ '''Mouse - Primordial Germ Cell Migration'''
|-
| [[File:Primordial germ cell 001 icon.jpg|120px|link=Quicktime_Movie_-_Primordial germ cell migration 01]]
| [[File:Primordial germ cell 002 icon.jpg|120px|link=Quicktime_Movie_-_Primordial germ cell migration 02]]
| [[File:Primordial germ cell 003 icon.jpg|120px|link=Quicktime_Movie_-_Primordial germ cell migration 03]]
|-bgcolor="a3bfb1"
| E9.0 Migration
| E9.5 Migration
| E10.5 Migration
|-bgcolor="F5FFFA"
| [[Quicktime_Movie_-_Primordial germ cell migration 01|Quicktime]] | [[Movie_-_Primordial germ cell migration 01|Flash]]
| [[Quicktime_Movie_-_Primordial germ cell migration 02|Quicktime]] | [[Movie_-_Primordial germ cell migration 02|Flash]]
| [[Quicktime_Movie_-_Primordial germ cell migration 03|Quicktime]] | [[Movie_-_Primordial germ cell migration 03|Flash]]
|-
|}

* '''Not the primordial germ cells which respond to SRY''' presence or absence, but the supporting cells within the developing gonad.
** Germ cells occasionally migrate by mistake into the developing adrenal gland and in the absence of sertoli cells telling them what to do, abnormally begin to develop as oocytes, even in males

:'''Links:''' [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A4665&rendertype=figure&id=A4669 Germ cell migration pathway]

===Gametogenesis===
* forming PGCs as a small population of migratory cells
* enter the gonad where they undergo several rounds of mitotic cell division
* female - the germ cells enter meiosis and become arrested at the dictyate (diplotene) stage of meiotic prophase 1. All oocytes are at this stage at birth
* male - the germ cells are enclosed by the developing Sertoli cells and are induced to arrest differentiation and cell division as T1 prospermatogonia until after birth.

:'''Links:''' [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3729&rendertype=figure&id=A3735 Image - Spermatogenesis] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A4695&rendertype=figure&id=A4715 Image -Oogenesis]

==3. Differentiation of internal genital organs and ducts==
[[File:Stage_22_Urogenital_1l.jpg]]

Human embryo (Carnegie stage 22, week 8) pelvic level cross-section.
===Male===
{|
| valign="top" | This looped animation shows the development of the male gonad showing medullary sex cords.

* The paramesonephric duct (red, left) degenerates under the influence of anti-Mullerian hormone (AMH) secreted by sertoli cells.
* The mesonephric duct (purple) is maintained and differentiates under the influence of Testosterone secreted by Leydig cells. Within the testes these mesonephric tubules grow towards the testis cords and will form the rete testis. The mesonephric duct extending out of the gonad forms the ductus deferens.
* The testis cords (orange) containing the Sertoli cells and the germ cells (which are arrested as T1 prospermatogonia until after birth) later differentiate into seminiferous tubules which become hollow and actively produce spermatazoa during puberty.

The tunica albuginea (white) covers the testis and bands extend inward to form connective tissue septa.
|
{{Testis movie}}
|}

===Anti-Mullerian Hormone===
Anti-Mullerian hormone (AMH) or Mullerian Inhibiting Substance (MIS) hormone with at least two gonadal related functions:
* In males, it is produced by embryonic Sertoli cells and causes the loss of the paramesonephric (Mullerian) duct system that forms the internal female genital tract.
* In females, it is produced after puberty by follicle cells and suppresses the development of other primary follicles, thus restricting the number of follicles stimulated by FSH.

===Female===
{|
| valign="top" | This looped animation shows the development of the female gonad showing cortical sex cords.

* The mesonephric duct (purple) degenerates, small remnants may remain as epoophoron and paroophoron (in the mesentry of the ovary) and Gartner's cycts (near vagina).
* The paramesonephric duct (red, left) grows forming the oviducts (fallopian tubes) and the end opens into the peritoneal cavity and terminates in fimbria (finger-like extensions). Away from the ovary, the two paramesonephric ducts fuse in the midline to form the uterus.
* After entry of the germ cell into meiosis they are called oocytes and they are surrounded by the derivatives of the supporting cell lineage - the follicle cells or granulosa cells.
* About 95% of the germ cells that entered meiosis in the female will be lost by a process called follicular atresia (see graph. Only about 400,000 remain at the time of puberty.

[[File:Infant ovary.jpg|300px]] [[File:Human_ovary_non-growing_follicle_model.jpg|300px]]
| {{Ovary movie}}
|}

===Uterus Development===

* '''Week 7''' – duct preservation or regression begins

{{Uterus movie}}

Paramesonephric duct development

===Vagina Development===

* The embryonic origin of the vagina has been a historically hotly debated issue with several different contributions and origins described.
* Current molecular studies show the whole vagina is derived from the intermediate mesoderm-derived Müllerian duct (see review <ref><pubmed>19598112</pubmed></ref>)
** bone morphogenic protein 4 (BMP4) reshapes the duct into the vaginal primordium.
* exhibits different features from the uterus
** stratified squamous epithelium
** insensitivity to anti-Müllerian hormone

:'''Links:''' [[Vagina Development]]

==4. Differentiation of External Genitalia==
[[File:Gray1119.jpg|thumb|Historic diagram of external development]]
[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A972&rendertype=box&id=A1026 Endocrinology - Diagram of the development of the external genitalia] | [http://www.ncbi.nlm.nih.gov/books/NBK29/bin/ch6fb5.jpg image]

* external genitalia are initially identical and undergo male and female differentiation under the influence or absence of steroidal sex hormones.
* Indifferent stage ‐ cloaca divided by proliferating mesenchyme forming the urorectal septum which separates the ventral urogenital sinus from the dorsal rectum.
* Difference stage ‐ locally in this region the presence or absence of '''dihydrotestosterone''' (DHT), generated from testosterone, determines male/female development.

===Dihydrotestosterone (DHT)===
[[File:Testosterone_metabolism.jpg|thumb|Testosterone metabolism]]
* Male presence of DHT
** locally in this region leads to '''genital tubercle''' growth, form
** '''genital folds''' (urethral) initial maintenance and then fusion, forming perineal and penile raphe.
** '''labioscrotal swellings''' (lateral to urethreal folds) become the scrotum.
* Female absence of DHT
** genital tubercle remains small, bends caudally to form the clitoris.
** genital folds (urethral) persist, do not fuse, and form labia minora.
** open urogenital sinus forms a cleft into which urethra and vagina open.
** labioscrotal swellings become the labia majora.

===Female===
[[File:Newborn_uterus.jpg|thumb|Newborn uterus]]
This looped animation shows the development of external female genitalia from the indifferent external structure, covering the approximate period of week 9 to 12.

{{Female external movie}}

[[File:Urogenital_septum_001 icon.jpg|90px|link=Development_Animation_-_Urorectal_Septum]]

[[Development_Animation_-_Urogenital_Septum|Animation - Urorectal septum and division of the cloacal membrane]]

Note the original cloacal membrane becomes separated into the urogenital membrane and anal membrane. The urogenital folds beneath the genital tubercle remain separate (unfused), forming the inner labia minora and second outer skin folds form the larger labia majora either side of the developing vestibule of the vagina. Note at the top of the animation, the changing relative size of the genital tubercle as it forms the glans of the clitoris.

===Male Genitalia Development===
[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A972&rendertype=box&id=A1027 Endocrinology - Box 6.6 The roles of testosterone (T) and 5α-dihydrotestosterone (DHT)]

This looped animation shows the development of external male genitalia from the indifferent external structure, covering the approximate period of week 9 to 12.

{{Male external movie}}

==Gonad Descent==
{|
|
* Both kidney and gonads develop retroperitoneally, with the gonads moving into the abdomen or eventually into the scrotal sacs.
* During fetal development the gubernaculum and fetal growth in both male and female, changes the gonads’ relative positions finally reaching their adult locations.

Both female and male gonads undergo anatomical descent.

* '''Ovaries''' ‐ undergo caudal and lateral shifts to be suspended in the broad ligament of the uterus, gubernaculum does not shorten, it attaches to paramesonephric ducts, causing medial movement into the pelvis.

* '''Testes''' ‐ two anatomical phases in descent, transabdominal and transinguinal, under the influence of the shortening gubernaculum.
| {{Testis descent movie}}
|}

{|
| [[File:Testis_001 icon.jpg|200px|link=Development_Animation_-_Testis_Descent]]
| [[File:Testis-descent start.jpg|300px]] [[File:Testis-descent end.jpg|300px]]

:'''Links:''' [[Media:Testis Descent_001.mov‎|Quicktime movie]] | [[Quicktime Development Animation - Testis Descent|Quicktime]] | [[Development Animation - Testis Descent|Flash]] | [[Testis Development]] | [[Third Trimester]]
|}

The testis (white) lies in the subserous fascia (spotted) a cavity processus vaginalis evaginates into the scrotum, and the gubernaculum (green) attached to the testis shortens drawing it into the scrotal sac. As it descends it passes through the inguinal canal which extends from the deep ring (transversalis fascia) to the superficial ring (external oblique muscle). Descent of the testes into the scrotal sac begins generally during week 26 and may take several days. The animation shows the path of a single testis.

Data from a recent study of male human fetal (between 10 and 35 weeks) gonad position.

* 10 to 23 weeks - (9.45%) had migrated from the abdomen and were situated in the inguinal canal
* 24 to 26 weeks - (57.9%) had migrated from the abdomen
* 27 to 29 weeks - (16.7%) had not descended to the scrotum

Incomplete or failed descent can occur unilaterally or bilaterally, is more common in premature births, and can be completed postnatally.

==5. Postnatal - Puberty==
[[File:Puberty_growth.jpg|thumb|Puberty growth]]
Puberty can occur over a broad range of time and differently for each sex:
* girls (age 7 to 13)
* boys (age 9 to 15)

The physical characteristics that can be generally measured are: genital stage, pubic hair, axillary hair, menarche, breast, voice change and facial hair.

===Male===
* Testosterone - adult testes produce about 6-10 mg /day in males (~0.5 mg / day in females) carried in circulation by a specific carrier globulin.
* masculinizing androgen - also at puberty, spermatogenesis in males
* development of secondary sexual characteristics - body and facial hair growth (male pattern baldness)
* anabolic effect - metabolism towards conservation of amino acids, promoting protein synthesis, muscle development
* neural - libido in both sexes, male pattern behaviour
* Sustentacular (Sertoli) cells - produce anti-mullerian hormone (AMH) to puberty.
** '''AMH''' - anti-Müllerian hormone (Müllerian inhibiting factor (MIF), Müllerian-inhibiting hormone (MIH), and Müllerian-inhibiting substance (MIS)).
[[File:Male_testosterone_and_AMH_level_graph.jpg|500px]]

===Female===
[[File:XXhpgaxis.jpg|thumb|Female HPG Axis]]
In females, menarche (the first menstruation or a period) usually occurs after the other secondary sex characteristics, and will continue until menopause (permanent cessation of reproductive fertility).

The diagram shows the hormonal regulation pathway from the brain to the ovary and subsequent impact on uterine changes during the menstral cycle.

* '''GnRH''' = Gonadotropin-releasing hormone (GnRH). This peptide hormone is a decapeptide (10 amino acids) with a short half life (<15 minutes).
* '''LH''' = Luteinizing Hormone
* '''FSH''' = Follicle Stimulating Hormone

A similar endocrine axis is also found for regulation of the male gonad.

<gallery>
File:HPG female axis.jpg|Hypothalamus - Pituitary - Gonad (female)
File:HPG male axis.jpg|Hypothalamus - Pituitary - Gonad (male)
</gallery>

===Puberty Abnormalities===
* '''Precocious Puberty''' - Premature development of the signs of puberty which can occur in both girls (before age 7 or 8) and in boys (before age 9).
* '''Delayed Puberty''' - Determined in boys by a lack of increase in testicular volume by the age of 14 years. In girls, no breast development by the age of 13.5 years and a lack of menstruation by the age of 16 years. There can also be a "pubertal arrest" where there is no progress in puberty over 2 year period.

==Sex Differences in Adult and Developing Brains==

* not known significance of brain sex differences
* transient sex differences in gene expression in developing brains may cause permanent differences in brain structure
* may prevent as well, by compensating for potentially differentiating effects of sex differences in gonadal hormone levels and sex chromosomal gene expression

* Brains of males and females differ
** in regions specialized for reproduction
** in other regions (controlling cognition, etc) where sex differences are not necessarily expected
** Differentially susceptible to neurological and psychiatric disease

2 sources of sexually dimorphic information
* complement of sex chromosome genes
* mix of gonadal hormones

==Abnormalities==

===Sex Reversal===
* Where chromosomal sex does not match phenotypic sex i.e. XX males or XY females

XX males - usually caused by a transfer of some Y chromosome DNA onto the X chromosome
* Gonads develop as testes, everything looks normal internally and externally but infertile due to a failure of spermatogenesis
* Similar to Kleinfelters syndrome (XXY)

XY females - usually steroidal origin
* Main cause is Androgen Insensitivity Syndrome (AIS) Complete (CAIS) Partial (PAIS) and Mild (MAIS) usually caused by mutations of the gene encoding the androgen receptor ''AR'' gene located on the X chromosome
* 5-alpha-reductase deficiency - again leads to a lack of complete steroidal induction of external genitalia
* Rare mutations in key sex determining genes including deletion or mutations of ''SRY''

Human genital abnormalities are currently described as "Disorders of Sex Development" (DSD) and include: chromosomal, gonadal dysfunction, tract abnormalities, external genitalia and gonadal descent.

:'''Links:''' [[Genital System - Abnormalities]]

===Congenital adrenal hyperplasia===
* impairment of cortisol production by the adrenal cortex, is one of the most common causes of intersex genitalia at birth
* genetically male (XY) infants born with undervirilized genitalia are often assigned and reared as girls.

===Cryptorchidism===
[[File:Cryptorchidism.jpg|thumb|Cryptorchidism]]
* abnormality of either unilateral or bilateral testicular descent, occurring in up to 30% premature and 3-4% term males.
* Descent may complete postnatally in the first year, failure to descend can result in sterility.

Testis descent is thought to have 2 phases:
# transabdominal descent - dependent on insulin-like hormone 3 (INSL3).
# inguinoscrotal descent - dependent on androgens.

===Undescended Ovaries===
* reasonably rare gonad abnormality, often detected following clinical assessment of fertility problems and may also be associated with other uterine malformations (unicornuate uterus).
* Due to the relative positions of the male (external) and female (internal) gonads and the pathways for their movement, failure of gonad descent is more apparent and common in male cryptorchidism than female undescended ovaries.

===Hydrocele===
* Male Hydrocele is a fluid-filled cavity of either testis or spermatic cord, where peritoneal fluid passes into a patent processus vaginalis.
* Female Hydrocele is a similar, but rarer, fluid-filled cavity occuring in the female as a pouch of peritoneum extending into the labium majorum (canal of Nuck).

===Tract Abnormalities===

Many different forms
* Uterine: associated with other anomolies, unicornuate uterus
* Vagina: agenesis, atresia
* Ductus Deferens: Unilateral or bilateral absence, failure of mesonephric duct to differentiate

{|
| [[File:Uterine abnormalities.jpg|400px]]
| [[File:Unicornate uterus.jpg|400px|Unicornate uterus]]
|-
| Uterine abnormalities
| Unicornate uterus
|}

Uterine Duplication (uterus didelphys, double uterus, uterus didelphis) A rare uterine developmental abnormality where the paramesonephric ducts (Mullerian ducts) completely fail to fuse generating two separate uterus parts each connected to the cervix and having an ovary each.

Septate Uterus

Cervical: cervical agenesis, cervical duplication

Vaginal: Mayer-Rokitansky syndrome (MRK anomaly, Rokitansky-Küster-Hauser syndrome, RKH syndrome, RKH) congenital absence of the vagina, dyspareunia, vaginal agenesis.

==External Genitalia - Hypospadia==

* most common penis abnormality (1 in 300) from a failure of male urogenital folds to fuse in various regions and resulting in a proximally displaced urethral meatus.
* The cause is unknown, but suggested to involve many factors either indivdually or in combination including: familial inheritance, low birth weight, assisted reproductive technology, advanced maternal age, paternal subfertility and endocrine-disrupting chemicals. Infants with hypospadias should not undergo circumcision.

==Movies==

{| border='0px'
|-
| [[File:Urogenital_sinus_001 icon.jpg|90px|link=Quicktime Development_Animation_-_Urogenital_Sinus]]
| [[File:Urogenital_septum_001 icon.jpg|90px|link=Quicktime Development_Animation_-_Urogenital_Septum]]
| [[File:Gonad-icon.jpg|90px|link=Quicktime Development Animation - Ovary‎‎]]
| [[File:Gonad-icon.jpg|90px|link=Quicktime Development Animation - Testis‎‎]]
| [[File:Female_external_001 icon.jpg|90px|link=Quicktime Development_Animation_-_Genital_Female_External]]
| [[File:Male_external_001 icon.jpg|90px|link=Quicktime Development_Animation_-_Genital_Male_External]]
| [[File:Uterus_001 icon.jpg|90px|link=Quicktime Development_Animation_-_Uterus]]
| [[File:Testis_001 icon.jpg|90px|link=Quicktime Development_Animation_-_Testis_Descent]]
|-bgcolor="a3bfb1"
|  '''Urogenital Sinus'''
|  '''Urogenital Septum'''
|  ‎‎'''Ovary'''
|  '''Testis'''‎‎
|  '''Female External'''
|  '''Male External'''
|  '''Uterus'''
|  '''Testis Descent'''
|-bgcolor="F5FFFA"
| [[Quicktime Development_Animation_-_Urogenital_Sinus|Quicktime]] | [[Development_Animation_-_Urogenital_Sinus|Flash]]
| [[Quicktime Development_Animation_-_Urogenital_Septum|Quicktime]] | [[Development_Animation_-_Urogenital_Septum|Flash]]
| [[Quicktime Development Animation - Ovary|Quicktime]] | [[Development Animation - Ovary|Flash]]
| [[Quicktime Development Animation - Testis|Quicktime]] | [[Development Animation - Testis|Flash]]
| [[Quicktime Development_Animation_-_Genital_Female_External|Quicktime]] | [[Development_Animation_-_Genital_Female_External|Flash]]
| [[Quicktime Development_Animation_-_Genital_Male_External|Quicktime]] | [[Development_Animation_-_Genital_Male_External|Flash]]
| [[Quicktime Development_Animation_-_Uterus|Quicktime]] | [[Development_Animation_-_Uterus|Flash]]
| [[Quicktime Development_Animation_-_Testis_Descent|Quicktime]] | [[Development_Animation_-_Testis_Descent|Flash]]
|}

== References ==
<references/>
===Textbooks===
* '''Before We Are Born''' (5th ed.) Moore and Persaud Chapter 14 p289-326
* '''Essentials of Human Embryology''', Larson Chapter 10 p173-205
* '''Human Embryology''', Fitzgerald and Fitzgerald Chapter 21-22 p134-152

===Online Textbooks===
* '''Developmental Biology''' (6th ed.) Gilbert Chapter 14 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.section.3498 Intermediate Mesoderm]
* Historic - '''Text-Book of Embryology'''. Bailey, F.R. and Miller, A.M. (1921). New York: William Wood and Co. [[Book_-_Text-Book_of_Embryology_15#The_Genital_Glands|Chapter 15. The Genital Glands]]

===Reviews===
<pubmed>17237341</pubmed>| [http://physrev.physiology.org/content/87/1/1.long Physiol. Rev.] | [[Talk:BGD_Lecture_-_Sexual_Differentiation#Figure_Pages|Figure Links]]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=genital+development genital development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=gonad+development gonad development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=sex+determination sex determination]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=genital+development genital development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=gonad+development gonad development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=sex+determination sex determination]

==External Links==
{{External Links}}

* '''Embryo Images Unit:''' [http://www.med.unc.edu/embryo_images/unit-genital/genital_htms/genitaltoc.htm Urongenital Development] | [http://www.med.unc.edu/embryo_images/unit-genital/genital_htms/genital008.htm Internal Genitalia] | [http://www.med.unc.edu/embryo_images/unit-genital/genital_htms/genital017.htm Definitive Kidney] | [http://www.med.unc.edu/embryo_images/unit-genital/genital_htms/genital020.htm External Genitalia]

* '''Histology:''' [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/MaleRepro/malerepro.htm Male Reproductive System] | [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/FemaleRepro/femalerepro.htm Female Reproductive System]

Lecture - Renal Development

2013-09-23T02:29:59Z

Z3283213:

==Introduction==
[[File:Gray1127.jpg|thumb|Historic drawing of adult kidney]]
{|
| width=380px|<mediaplayer width='360' height='500' image="http://embryology.med.unsw.edu.au/embryology/images/f/fe/Urogenital_sinus_001_icon.jpg">File:Urogenital_sinus_001.mp4</mediaplayer>

[[Urogenital Sinus Movie]]
|
'''Urogenital Sinus and Renal Development'''

This animation gives an overview of both early renal and genital (urogenital) development associated with the urogenital sinus.

The paired adult kidneys filter blood, excrete waste, reabsorb water and have endocrine functions. In the embryo, there are several stages in their development closely linked to genital development. The nephron, the functional unit of the kidney, is also a classical epithelial/mesenchyme type of interaction.

The urinary system is developmentally and anatomically associated with genital development, often described as the urogenital system.

{{Renal overview movie}}

|}

{|

|}

==Objectives ==
[[File:Stage 13 kidney sections.jpg|right]]
* Understand the 3 main stages of kidney development.
* Understand development of the nephron and renal papilla.
* Brief understanding of the mechanisms of nephron development.
* Understand the development of the cloaca, ureter and bladder.
* Brief understanding of abnormalities of the urinary system.

Lecture Date: 2013-09-24 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Renal.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

|}

==Textbooks==
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| '''Citation:''' UNSW Embryology 12th ed. Hill, M.A. Sydney, UNSW 2012

{{Renal Links}} | [[2010_Lecture_15|2010 Lecture]]
|}

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00012-6 Chapter 12 - Urogenital System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10015-6 Chapter 15 - Development of the Urogenital System]
|}

:'''Links:''' [[Embryology Textbooks]]

== Background==
* Mesoderm then intermediate mesoderm
* Vascular Development
* Gastrointestional
* Cloacal development
* Endocrine - covered in future lecture/lab

==Movies==

{{Renal cartoons}}

==Renal Anatomy==
[[File:Nephron histology.jpg|thumb|Nephron histology]]
{|
| '''Kidney'''
* Nephron - Functional unit of kidney
* Humans up to 1 million
* Filtration of waste from blood
* Endocrine
* Blood pressure regulation
| '''Ureter'''
* Urine transport to bladder
'''Urinary Bladder'''
* Urine storage
'''Urethra'''
* Urine transport to bladder
|
Germ layers
* Endoderm - lining bladder also lines allantois
* Mesoderm - Intermediate mesoderm (lies between somites and lateral plate)
* Ectoderm - innervation
|}

==Intermediate Mesoderm==
[[File:Stage7_intermediate-mesoderm.jpg|thumb|Week 3 intermediate mesoderm]]
* development occurs laterally symmetrical (left right)
* intermediate mesoderm lying beside the '''dorsal aorta'''
* initially form '''mesonephric tubules''' (epithelial)
* these tubules connect to a common duct, '''mesonephric duct'''
* the mesonephric duct then extends within the mesoderm, rostro-caudally
* eventually making contact with the '''cloaca'''

==Mesonephric Duct==

Later in development, both the mesonephric duct and the cloaca both continue to differentiate and undergo extensive remodelling (and renaming)

===Uteric Bud===

* arise near the cloacal connection of the mesonephric duct
* branch from the mesonephric duct laterally into the intermediate mesoderm
* induce the surrounding mesoderm to differentiate - metanephric blastema
** this mesoderm will in turn signal back to differentiate the uteric bud

'''Epithelial - mesenchymal interaction'''

Uteric Bud forms - ureter, pelvis, calyces, collecting ducts

===Metanephric Blastema===

* forms glomeruli, capsule, nephron tubules
* this development continues through fetal period

==Nephros Development==
The 3 main stages and pairs during development:

# pronephros
# mesonephros
# metanephros

===Pronephros===
* week 4 few cells in cervical region fish
* Human E18, Mouse E7.5 - pronephric duct forms first with associated nephrogenic mesenchyme
* grows rostro caudally cervical -> cloaca
* E22 nephrogenic mesenchyme differentiates to form pronephroi not functional in mammals degenerates rapidly

===Mesonephros===
[[File:Stage 13 kidney sections 2.jpg|thumb|Stage 13 mesonephros]]
[[File:Stage22 mesonephros.jpg|thumb|Stage 22 mesonephros]]
* Human E24, Mouse E9.5 caudal to pronephros
* forms by induction from pronephros
* pronephric duct now becomes mesonephric duct (also called Wolffian Duct)

===Metanephros===
* Human E35-37, Mouse E11 epithelia bud at end of mesonephric duct uteric bud and associated metanephric mesenchyme
{|
| {{Urogenital stage 22 movie}}
| {{Gastrointestinal stage 13 movie}}
|}

===Uteric Bud===
* induced by metanephric mesenchyme to differentiate
* forms collecting tubules, renal pelvis, ureter
* metanephric mesenchyme induced by uteric to differentiate forms nephron

===Week 5 and Week 8===
{|

| [[File:Stage 13 image 081.jpg|400px]]
| [[File:Stage_22_image_188.jpg|400px]]
|-
| Embryo Stage 13 mesonephros (week 5)
| Embryo Stage 22 metanephros (week 8)
|}

[[File:Stage_22_image_189.jpg|400px]]

===Fetal===
[[File:Fetal_10wk_urogenital_1.jpg|thumb|early fetal kidney]]

<gallery>
File:Human_fetal_kidney_histology_01.jpg
File:Human_fetal_kidney_histology_02.jpg
File:Human_fetal_kidney_histology_03.jpg
File:Human_fetal_kidney_histology_04.jpg
</gallery>

== Nephron ==
[[File:Gray1128.jpg|thumb|Adult nephron structure]]
[[File:Nephron histology.jpg|thumb|Nephron histology]]

{| border='0px'
|-
{{Nephron movie}}
| valign="top" |'''Early Renal Development'''

'''Legend'''

* '''Uteric Bud''' - developing ureter, pelvis, calyces, collecting ducts
* '''Metanephric Blastema''' (intermediate mesoderm) - developing glomeruli, capsule, nephron tubules

Development has four developmental stages:
# '''vesicle''' (V) stage (13-19 weeks)
# '''S-shaped body''' (S) stage ( 20-24 weeks)
# '''capillary loop''' (C) stage (25-29 weeks)
# '''maturation''' (M) stage (infants aged 1-6 months)

'''Links:''' [[Quicktime Development Animation - Renal|Quicktime version]] | [[Development Animation - Urogenital Sinus|Animation - Urogenital Sinus]] | [[Renal System Development]]
|-
|}

===Nephron Development===
* disorganised mesenchymal cells become a highly organised epithelial tubule
* Condensation - groups of about 100 cells condense tightly together to form a distinct mass
* Epithelialisation - condensed cells lose their mesenchymal character and gain epithelial
* At end of this period formed a small epithelial cyst complete with a basement membrane, cell-cell junctions and a defined cellular apico-basal polarity.

===Early morphogenesis===
[[File:Renal - podocyte development 01.jpg|thumb|Renal - podocyte development]]
* cyst invaginates twice to form a comma
* then a S-shaped body one invagination site later becomes the glomerular cleft
* At about this time blood vessel progenitors invade cleft to begin construction of vascular component of glomerulus
* Tubule maturation specialised transporting segments of nephron differentiate complex of convoluted tubules is created

[[File:Glomerular podocyte cartoon.jpg|500px]]

===Adult nephron structure===
* mean glomerular number shown to level at 36 weeks
** about 15,000 at 15 weeks
** about 740,000 at 40 weeks.

* key structure of the adult nephron is the glomerulus (renal corpuscle), which represents the vascular/renal interface.

<gallery>
File:Nephron_histology_01.jpg|Glomerulus structure
File:Nephron_histology_02.jpg|Vascular and renal poles
</gallery>

'''Related Images:''' [[:File:Nephron_histology.jpg|Nephron histology overview]] | [[:File:Nephron_histology 01.jpg|glomerulus structure]] | [[:File:Nephron_histology 02.jpg|vascular and renal poles]]

==Renal Vascular==
===Renal Arteries===
{|
| {{Renal vascular movie}}
|
* starts in week 5 and is completed by week 15.
* week 6 - the kidneys begin to change their relative position, described as "ascent of the kidneys", to their correct anatomical position.
* week 9 - the rising movement is completed.
* During the ascent, the kidneys also become vascularised via the dorsal aorta.
* As this ascent occurs, the mesonephric ducts and the ureters enter the wall of the developing bladder.
|}
* Arise with ascent and inferior branches lost
* Sequential, 25% population have 2 or more renal arteries
* branch of abdominal aorta, divides into 4-5 branches
** each gives off small branches to suprarenal glands, ureter, surrounding cellular tissue and muscles
* Frequently a second renal artery (inferior renal) from abdominal aorta at a lower level, supplies lower portion of kidney.

===Renal Venous===
{|
| [[File:Embryo_renal_venous_cartoon.jpg|300px]]
| [[File:Adult_renal_venous_cartoon.jpg|300px]]
|-
| Embryo renal venous
| Adult renal venous
|}

==Endocrine Kidney==
Covered also in Endocrine Development lecture
* Renin - Increase Angiotensin-aldosterone system
* Prostaglandins - decrease Na+ reabsorption
* Erythropoietin - Increase Erythrocyte (rbc) production
* 1,25 (OH)2 vitamin D - Calcium homeostasis
* Prekallikreins - (plasma protein inactive precursor of kallikrein) Increase kinin production (altered vascular permeability)

==Cloaca==
[[File:Endoderm_cartoon.jpg|File:Endoderm development]]
* hindgut region ending at the cloacal membrane
* divided (ventro-dorsally) by the urogenital septum
** ventral - common urogenital sinus
** dorsal - rectum

{| border='0px'

|-
| {{Renal overview movie}}
| {{Urogenital_septum_movie}}
|}

===Common urogenital sinus===
* superior end continuous with '''allantois'''
* common urogenital sinus and mesonephric duct fuse (connect)
* differentiates to form the bladder
* inferior end forms '''urethra'''
** this will be different in male and female development

===Urinary Bladder===
[[File:Adult_bladder.jpg‎|thumb|Adult bladder]]
* early origins of the bladder at the superior end of the common urogenital sinus
*8 open inferiorly to the cloaca and superiorly to the allantois
* Septation of the claoca - divides the anterior region to the primordial bladder component from the posterior rectal component.
* associated ureters and urethra

Dorsal view of developing bladder

[[Media:Trigone_3.mov|Trigone formation animation]]

* Ultrasound measurement of the bladder size can be used as a diagnostic tool for developmental abnormalities.

===Bladder Structure===
[[File:Bladder histology.jpg|thumb|Bladder histology]]
Can be described anatomically by its 4 layers from outside inward:
* Serous - the superior or abdominal surfaces and the lateral" surfaces of the bladder are covered by visceral peritoneum, the serous membrane (serosa) of the abdominal cavity, consisting of mesthelium and elastic fibrous connective tissue.
* Muscular - the detrusor muscle is the muscle of the urinary bladder wall.
* Submucosa - connects the muscular layer with the mucous layer.
* Mucosa - (mucus layer) a transitional epithelium layer formed into folds (rugae).

===Detrusor Muscle===
* The adult detrusor muscle consists of three layers of smooth (involuntary) muscle fibres.
** external layer - fibres arranged longitudinally
** middle layer - fibres arranged circularly
** internal layer - fibres arranged longitudinally

===Ureter Development===
* The adult ureter is a thick-walled muscular tube, 25 - 30 cm in length, running from the kidney to the urinary bladder.
* Anatomically can be described in two parts the abdominal part (pars abdominalis) and pelvic part (pars pelvina).
* The ureter is composed of three layers: outer fibrous layer (tunica adventitia), muscular layer (tunica muscularis) and mucous layer (tunica mucosa).
* The muscular layer can also be subdivided into 3 fibre layers: an external longitudinal, a middle circular, and an internal longitudinal.

===Urethra Development===
* Further development of the urinary system varies depending on the sex of the embryo.
* Males - the pelvic urethra forms the membranous urethra, the prostatic urethra and penile urethra. (The sex of the above animation and sections is male)
* Females - the pelvic urethra forms the membranous urethra and the vestibule of the vagina.

==Abnormalities==
[[File:Australian_abnormalities_pie_urogen.png|thumb]]
===Horseshoe Kidney===

{|
| [[File:Horseshoe kidney.jpg|400px]]
|
* fusion of the lower poles of the kidney.
* During migration from the sacral region the two metanephric blastemas can come into contact, mainly at the lower pole.
* The ureters pass in front of the zone of fusion of the kidneys.
* The kidneys and ureters usually function adequately but there is an increased incidence of upper urinary tract obstruction or infection.
* Some horseshoe variations have been described as having associated ureter abnormalities including duplications.
|}
===Kidney Vascular===
Supernumerary renal arteries

[[File:Accessory_renal_artery.jpg|300px]] [[File:Multiple_renal_arteries_01.jpg|300px]]

Supernumerary renal vein

[[File:Supernumerary_renal_vein_02.jpg|300px]] [[File:Supernumerary_renal_vein_04.jpg|300px]]

===Urorectal Septum Malformation===
* thought to be a deficiency in caudal mesoderm which in turn leads to the malformation of the urorectal septum and other structures in the pelvic region.
* Recent research has also identified the potential presence of a persistent urachus prior to septation of the cloaca (common urogenital sinus).

===Bladder===
* absent or small bladder -
associated with renal agenesis.

===Bladder Exstrophy===
[[File:Bladder_Exstrophy.jpg|thumb|Bladder_Exstrophy]]
* developmental abnormality associated with bladder development.
* origins appear to occur not just by abnormal bladder development, but by a congenital malformation of the ventral wall of abdomen (between umbilicus and pubic symphysis).
* There may also be other anomolies associated with failure of closure of abdominal wall and bladder (epispadias, pubic bone anomolies).

===Ureter and Urethra===
* Ureter - Duplex Ureter
* Urethra- Urethral Obstruction and Hypospadias

===Polycystic Kidney Disease===
[[File:Multicystic kidney.jpg|thumb|Multicystic kidney]]
* diffuse cystic malformation of both kidneys
* cystic malformations of liver and lung often associated, Often familial disposition
* Two types
** Infantile (inconsistent with prolonged survival)
** Adult (less severe and allows survival)
* Autosomal dominant PKD disease - recently identified at mutations in 2 different human genes encoding membrane proteins (possibly channels)

===Wilms' Tumor===
[[File:Wilms_tumor.jpg|thumb|Wilms' tumor]]
* (nephroblastoma) Named after Max Wilms, a German doctor who wrote first medical articles 1899
* most common type of kidney cancer children
* WT1 gene - encodes a zinc finger protein
* Both constitutional and somatic mutations disrupting the DNA-binding domain of WT1 result in a potentially dominant-negative phenotype
* some blastema cells (mass of undifferentiated cells) persist to form a ‘nephrogenic rest’
* Most rests become dormant or regress but others proliferate to form hyperplastic rests
* any type of rest can then undergo a genetic or epigenetic change to become a neoplastic rest
* can proliferate further to produce a benign lesion (adenomatous rest) or a malignant Wilms’ tumour

=== Prune Belly Syndrome ===
<gallery>
File:Hydronephrosis.jpg|
File:Renal_outflow_obstruction.jpg|
File:Prune_belly.jpg|Prune_belly
</gallery>
* lower urinary tract obstruction
* mainly male
* fetal urinary system ruptures leading to collapse and "prune belly" appearance.

==Additional Images==
<gallery>
File:Stage 11 historic-Atwell1930-3b.jpg|Stage 11 historic Atwell (1930)
File:Stage_11_historic-Heuser1930-1c.jpg|Stage 11 historic Heuser (1930)
File:Gray1128.jpg|Nephron structure
File:Nephron physiology.jpg|Nephron physiology
File:Gray1127.jpg|Kidney and adrenal gland (adult)
File:Endoderm cartoon.jpg|Endoderm cartoon
File:Fetal 10wk urogenital 1.jpg|Fetal urogenital region most lateral right
File:Fetal 10wk urogenital 2.jpg|Fetal urogenital region lateral right
File:Fetal 10wk urogenital 3.jpg|Fetal urogenital region medial
File:Fetal 10wk urogenital 4.jpg|Fetal urogenital region midline
File:Bladder_histology.jpg|Bladder histology
File:Australian_abnormalities_pie_urogen.png
File:Horseshoe kidney.jpg|Horseshoe kidney
File:Hydronephrosis.jpg|Hydronephrosis
File:Renal_outflow_obstruction.jpg‎|Renal outflow obstruction
File:Bladder Exstrophy.jpg‎|Bladder Exstrophy
</gallery>

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter 13 p303-346
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 10 p261-306
* '''Before We Are Born''' (5th ed.) Moore and Persaud Chapter14 p289-326
* '''Essentials of Human Embryology''', Larson Chapter 10 p173-205
* '''Human Embryology''', Fitzgerald and Fitzgerald Chapter 21-22 p134-152

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 Chapter 14 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.section.3498 Intermediate Mesoderm] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3498&rendertype=figure&id=A3500 Figure 14.18. General scheme of development in the vertebrate kidney] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6814 Figure 23-23. Mechanism of mesenchymal inductive effect on the ureteric bud] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3498&rendertype=figure&id=A3507 Figure 14.21. Ureteric bud growth is dependent on GDNF and its receptor]

* '''Molecular Cell Biology''' by Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. New York: W. H. Freeman & Co.; c1999 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6811 Reciprocal Epithelial-Mesenchymal Interactions Regulate Kidney Development] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6811 Figure 23-21. Embryonic development of the kidney]

===Reviews===
* Quaggin SE, Kreidberg JA. Development of the renal glomerulus: good neighbors and good fences. Development. 2008 Feb;135(4):609-20. [http://www.ncbi.nlm.nih.gov/pubmed/18184729 PMID: 18184729]
* Brenner-Anantharam A, Cebrian C, Guillaume R, Hurtado R, Sun TT, Herzlinger D. Tailbud-derived mesenchyme promotes urinary tract segmentation via BMP4 signaling. Development. 2007 May;134(10):1967-75. [http://www.ncbi.nlm.nih.gov/pubmed/17442697 PMID: 17442697]
* [http://www.nature.com/ng/meetings/nephrogenetics/index.html Forefronts Symposium on Nephrogenetics: from development to physiology March 8-11, 2007 Danvers, MA] A meeting to synthesize an integrated view of the normal development and function of the kidney from the genetic standpoint.
* Costantini F. Renal branching morphogenesis: concepts, questions, and recent advances. Differentiation. 2006 Sep;74(7):402-21. [http://www.ncbi.nlm.nih.gov/pubmed/16916378 PMID: 16916378]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=intermediate_mesoderm intermediate mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=kidney_development kidney development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=renal_development renal development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=ureteric+bud ureteric bud] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=nephron_development nephron development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=bladder+development bladder development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=intermediate_mesoderm intermediate mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=kidney_development kidney development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=renal_development renal development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=ureteric_bud ureteric bud] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=nephron_development nephron development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=bladder+development bladder development]

== Terms ==
* '''bladder exstrophy''' - A congenital malformation with bladder open to ventral wall of abdomen (between umbilicus and pubic symphysis) and may have other anomolies associated with failure of closure of abdominal wall and bladder (epispadias, pubic bone anomolies).
* '''blastema''' - Term used to describe a mass of undifferentiated cells.
* '''diabetes insipidus''' - The disorder is related to the hormone antidiuretic hormone (ADH, also called vasopressin) its synthesis, secretion, receptors and signaling pathway. In diabetes insipidus there is an excretion of large amounts (up to 30 litres/day) of a watery urine and an unremitting thirst.
* '''hydronephrosis''' - (congenital hydronephrosis, Greek, ''hydro'' = water) A kidney abnormality due to partial or complete obstruction at the pelvi-ureteric junction. This leads to a grossly dilated renal pelvis causing extensive renal damage before birth.
* '''hyperplastic rests''' - In kidney development, embryonic blastema cells can persist and proliferate to form a pool of cells, which under either genetic or epigenetic influence can then change to become a neoplastic rest. Normally the majority of nephrogenic rests either regress or become dormant.
* '''mesonephros''' - The second temporary stage of kidney development (pro-, meso-, meta-). The intermediate mesonephros develops and disappears with the exception of its duct, the '''mesonephric duct''', which will form the male reproductive duct system. In males, the mesonephric tubules go on to form the ducts of the testis. In females, these degenerate. A few mesonephric tubules remain as efferent ductules in the male and vestigial remnants in the female.
* '''mesonephric duct''' - (= Wollfian duct) An early developing urogenital duct running the length of the embryo that will differentiate and form the male reproductive duct system. In females this duct degenerates (some remnants may remain associated in broad ligament).
* '''metanephros''' - The adult kidney, third stage of mammalian kidney (pro-, meso-, '''meta-''') development within the intermediate mesoderm.
* '''metanephric cap''' - In kidney development, the intermediate mesoderm which surrounds the ureteric bud and will develop into nephrons.
* '''multicystic kidney''' - There is no functional kidney tissue present in the kidney and it is replaced by a multilocular cyst. This is non-familial and is produced by atresia of a ureter and is always unilateral.
* '''neoplastic rest''' - In kidney development, a neoplastic rest can develop under either genetic or epigenetic influence from a hyperplastic rest, originating from an embryonic blastema cell. Normally the majority of nephrogenic rests either regress or become dormant.
* '''nephrogenic rest''' - A kidney term used to describe the embryonic blastema cells which persist and under either genetic or epigenetic can change to become a neoplastic rest. These neoplastic rests can develop postnatally as a benign form (adenomatous rest) or a malignant [W.htm#Wilms_tumour Wilm's tumour] form. The rests are further characterised by the time of generation leading to different anatomical kidney locations: early intralobar nephrogenic rests (within the renal lobe) and late pelilobar nephrogenic rests (periphery of the renal lobe).
* '''nephron''' - (Greek, ''nephros'' = kidney) The functional unit of the kidney.
* '''nephros''' - (Greek, ''nephros'' = kidney) Term used to describe features associated with the kidney. (pronephros, mesonephros, metanephros, nephric, nephron, nephroblastoma).
* '''podocyte''' - (visceral epithelial cell) kidney glomerulus cell forming the main component of the glomerular filtration barrier.
* '''podocyte specific proteins''' - podocalyxin, glomerular epithelial protein-1, podocin, nephrin, synaptopodin, and alpha-actinin-4), podocyte synthesized proteins (vascular endothelial growth factor and novH), transcription factors (WT1 and PAX2).
* '''pronephros''' - (Greek, ''pro'' = before) The first temporary stage of kidney development (pro-, meso-, meta-). This forms the kidney of primitive fish and lower vertebrates. Kidney development occurs within the intermediate mesoderm interacting with endoderm. In humans, this very rudimentary kidney forms very early at the level of the neck. It is rapidly replaced by the mesonephros, intermediate stage kidney, differentiating in mesoderm beneath.
* '''proteinuria''' - The abnormal presence of protein in the urine and an indicator of diesease including diabetic kidney disease (DKD, diabetic nephropathy).
* '''renal''' - (Latin, ''renes'' = kidney) Term used in relation to the kidney and associated structures (renal pelvis, renal artery)
* '''ureter''' - The two ureters are hollow tubes that link and carries urine from kidney to the bladder. The tubes have a muscular wall lined with transitional epithelium.
* '''urethra''' - The single muscular tube that links and carries urine from the bladder to the exterior. In humans, the urethral length differs between the sexes (male longer, female shorter).
* '''urinary''' - Term used to describe all components of the kidney system including the bladder, ureters and urethra.
* '''urine''' - Term used to describe the liquid waste produced by the kidney, stored in the bladder and excreted from teh body through the urethra.
* '''urorectal septum''' - (URS) The structure which develops to separate the cloaca (common urogenital sinus) into an anterior urinary part and a posterior rectal part.
* '''Wilms' tumour''' - A form of kidney/renal cancer (nephroblastoma) named after Dr Max Wilms who first described the tumor. This childhood kidney cancer is caused by the inactivation of a tumour suppressor gene (BRCA2) or Wilms tumor-1 gene (Wt1) and is one of the most common solid tumors of childhood, occurring in 1 in 10,000 children and accounting for 8% of childhood cancers. Wt1 also required at early stages of gonadal development. (More? [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=194070 OMIM - Wilm's tumour] | [http://www.whonamedit.com/doctor.cfm/2109.html Dr Max Wilms])
* '''Wilms' tumor 1-associating protein''' - (WTAP) protein expressed in extraembryonic tissues and required for the formation of embryonic mesoderm and endoderm.
* '''Wolffian duct''' - (= mesonephric duct, preferred terminology), runs from the mesonephros to cloaca, differentiates to form the male vas deferens and in the female regresses. Named after Caspar Friedrich Wolff (1733-1794), a German scientist and early embryology researcher and is said to have established the doctrine of germ layers. (More? [http://www.whonamedit.com/doctor.cfm/2433.html Caspar Friedrich Wolff])

----

{{2012ANAT2341}}

----

[[Category:Renal]]

Lecture - Renal Development

2013-09-23T02:28:41Z

Z3283213:

==Introduction==
[[File:Gray1127.jpg|thumb|Historic drawing of adult kidney]]
{|
| width=380px|<mediaplayer width='360' height='500' image="http://embryology.med.unsw.edu.au/embryology/images/f/fe/Urogenital_sinus_001_icon.jpg">File:Urogenital_sinus_001.mp4</mediaplayer>

[[Urogenital Sinus Movie]]
|
'''Urogenital Sinus and Renal Development'''

This animation gives an overview of both early renal and genital (urogenital) development associated with the urogenital sinus.

The paired adult kidneys filter blood, excrete waste, reabsorb water and have endocrine functions. In the embryo, there are several stages in their development closely linked to genital development. The nephron, the functional unit of the kidney, is also a classical epithelial/mesenchyme type of interaction.

The urinary system is developmentally and anatomically associated with genital development, often described as the urogenital system.

{{Renal overview movie}}

|}

{|
| [[File:Podcast_icon.jpg|link=ANAT2341_Embryology_2012_Lecture_Recordings]]
| '''Lectopia Lecture Audio'''

[http://lectopia.telt.unsw.edu.au/lectopia/lectopia.lasso?ut=153&id=140236 Lecture 15 - Renal Development]

Lecture Date: 2012-09-18 Lecture Time: 11:00 Venue: BioMed E Speaker: Mark Hill

|}

==Objectives ==
[[File:Stage 13 kidney sections.jpg|right]]
* Understand the 3 main stages of kidney development.
* Understand development of the nephron and renal papilla.
* Brief understanding of the mechanisms of nephron development.
* Understand the development of the cloaca, ureter and bladder.
* Brief understanding of abnormalities of the urinary system.

{|
Lecture Date: 2013-09-24 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Renal.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

|}

==Textbooks==
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| '''Citation:''' UNSW Embryology 12th ed. Hill, M.A. Sydney, UNSW 2012

{{Renal Links}} | [[2010_Lecture_15|2010 Lecture]]
|}

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00012-6 Chapter 12 - Urogenital System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10015-6 Chapter 15 - Development of the Urogenital System]
|}

:'''Links:''' [[Embryology Textbooks]]

== Background==
* Mesoderm then intermediate mesoderm
* Vascular Development
* Gastrointestional
* Cloacal development
* Endocrine - covered in future lecture/lab

==Movies==

{{Renal cartoons}}

==Renal Anatomy==
[[File:Nephron histology.jpg|thumb|Nephron histology]]
{|
| '''Kidney'''
* Nephron - Functional unit of kidney
* Humans up to 1 million
* Filtration of waste from blood
* Endocrine
* Blood pressure regulation
| '''Ureter'''
* Urine transport to bladder
'''Urinary Bladder'''
* Urine storage
'''Urethra'''
* Urine transport to bladder
|
Germ layers
* Endoderm - lining bladder also lines allantois
* Mesoderm - Intermediate mesoderm (lies between somites and lateral plate)
* Ectoderm - innervation
|}

==Intermediate Mesoderm==
[[File:Stage7_intermediate-mesoderm.jpg|thumb|Week 3 intermediate mesoderm]]
* development occurs laterally symmetrical (left right)
* intermediate mesoderm lying beside the '''dorsal aorta'''
* initially form '''mesonephric tubules''' (epithelial)
* these tubules connect to a common duct, '''mesonephric duct'''
* the mesonephric duct then extends within the mesoderm, rostro-caudally
* eventually making contact with the '''cloaca'''

==Mesonephric Duct==

Later in development, both the mesonephric duct and the cloaca both continue to differentiate and undergo extensive remodelling (and renaming)

===Uteric Bud===

* arise near the cloacal connection of the mesonephric duct
* branch from the mesonephric duct laterally into the intermediate mesoderm
* induce the surrounding mesoderm to differentiate - metanephric blastema
** this mesoderm will in turn signal back to differentiate the uteric bud

'''Epithelial - mesenchymal interaction'''

Uteric Bud forms - ureter, pelvis, calyces, collecting ducts

===Metanephric Blastema===

* forms glomeruli, capsule, nephron tubules
* this development continues through fetal period

==Nephros Development==
The 3 main stages and pairs during development:

# pronephros
# mesonephros
# metanephros

===Pronephros===
* week 4 few cells in cervical region fish
* Human E18, Mouse E7.5 - pronephric duct forms first with associated nephrogenic mesenchyme
* grows rostro caudally cervical -> cloaca
* E22 nephrogenic mesenchyme differentiates to form pronephroi not functional in mammals degenerates rapidly

===Mesonephros===
[[File:Stage 13 kidney sections 2.jpg|thumb|Stage 13 mesonephros]]
[[File:Stage22 mesonephros.jpg|thumb|Stage 22 mesonephros]]
* Human E24, Mouse E9.5 caudal to pronephros
* forms by induction from pronephros
* pronephric duct now becomes mesonephric duct (also called Wolffian Duct)

===Metanephros===
* Human E35-37, Mouse E11 epithelia bud at end of mesonephric duct uteric bud and associated metanephric mesenchyme
{|
| {{Urogenital stage 22 movie}}
| {{Gastrointestinal stage 13 movie}}
|}

===Uteric Bud===
* induced by metanephric mesenchyme to differentiate
* forms collecting tubules, renal pelvis, ureter
* metanephric mesenchyme induced by uteric to differentiate forms nephron

===Week 5 and Week 8===
{|

| [[File:Stage 13 image 081.jpg|400px]]
| [[File:Stage_22_image_188.jpg|400px]]
|-
| Embryo Stage 13 mesonephros (week 5)
| Embryo Stage 22 metanephros (week 8)
|}

[[File:Stage_22_image_189.jpg|400px]]

===Fetal===
[[File:Fetal_10wk_urogenital_1.jpg|thumb|early fetal kidney]]

<gallery>
File:Human_fetal_kidney_histology_01.jpg
File:Human_fetal_kidney_histology_02.jpg
File:Human_fetal_kidney_histology_03.jpg
File:Human_fetal_kidney_histology_04.jpg
</gallery>

== Nephron ==
[[File:Gray1128.jpg|thumb|Adult nephron structure]]
[[File:Nephron histology.jpg|thumb|Nephron histology]]

{| border='0px'
|-
{{Nephron movie}}
| valign="top" |'''Early Renal Development'''

'''Legend'''

* '''Uteric Bud''' - developing ureter, pelvis, calyces, collecting ducts
* '''Metanephric Blastema''' (intermediate mesoderm) - developing glomeruli, capsule, nephron tubules

Development has four developmental stages:
# '''vesicle''' (V) stage (13-19 weeks)
# '''S-shaped body''' (S) stage ( 20-24 weeks)
# '''capillary loop''' (C) stage (25-29 weeks)
# '''maturation''' (M) stage (infants aged 1-6 months)

'''Links:''' [[Quicktime Development Animation - Renal|Quicktime version]] | [[Development Animation - Urogenital Sinus|Animation - Urogenital Sinus]] | [[Renal System Development]]
|-
|}

===Nephron Development===
* disorganised mesenchymal cells become a highly organised epithelial tubule
* Condensation - groups of about 100 cells condense tightly together to form a distinct mass
* Epithelialisation - condensed cells lose their mesenchymal character and gain epithelial
* At end of this period formed a small epithelial cyst complete with a basement membrane, cell-cell junctions and a defined cellular apico-basal polarity.

===Early morphogenesis===
[[File:Renal - podocyte development 01.jpg|thumb|Renal - podocyte development]]
* cyst invaginates twice to form a comma
* then a S-shaped body one invagination site later becomes the glomerular cleft
* At about this time blood vessel progenitors invade cleft to begin construction of vascular component of glomerulus
* Tubule maturation specialised transporting segments of nephron differentiate complex of convoluted tubules is created

[[File:Glomerular podocyte cartoon.jpg|500px]]

===Adult nephron structure===
* mean glomerular number shown to level at 36 weeks
** about 15,000 at 15 weeks
** about 740,000 at 40 weeks.

* key structure of the adult nephron is the glomerulus (renal corpuscle), which represents the vascular/renal interface.

<gallery>
File:Nephron_histology_01.jpg|Glomerulus structure
File:Nephron_histology_02.jpg|Vascular and renal poles
</gallery>

'''Related Images:''' [[:File:Nephron_histology.jpg|Nephron histology overview]] | [[:File:Nephron_histology 01.jpg|glomerulus structure]] | [[:File:Nephron_histology 02.jpg|vascular and renal poles]]

==Renal Vascular==
===Renal Arteries===
{|
| {{Renal vascular movie}}
|
* starts in week 5 and is completed by week 15.
* week 6 - the kidneys begin to change their relative position, described as "ascent of the kidneys", to their correct anatomical position.
* week 9 - the rising movement is completed.
* During the ascent, the kidneys also become vascularised via the dorsal aorta.
* As this ascent occurs, the mesonephric ducts and the ureters enter the wall of the developing bladder.
|}
* Arise with ascent and inferior branches lost
* Sequential, 25% population have 2 or more renal arteries
* branch of abdominal aorta, divides into 4-5 branches
** each gives off small branches to suprarenal glands, ureter, surrounding cellular tissue and muscles
* Frequently a second renal artery (inferior renal) from abdominal aorta at a lower level, supplies lower portion of kidney.

===Renal Venous===
{|
| [[File:Embryo_renal_venous_cartoon.jpg|300px]]
| [[File:Adult_renal_venous_cartoon.jpg|300px]]
|-
| Embryo renal venous
| Adult renal venous
|}

==Endocrine Kidney==
Covered also in Endocrine Development lecture
* Renin - Increase Angiotensin-aldosterone system
* Prostaglandins - decrease Na+ reabsorption
* Erythropoietin - Increase Erythrocyte (rbc) production
* 1,25 (OH)2 vitamin D - Calcium homeostasis
* Prekallikreins - (plasma protein inactive precursor of kallikrein) Increase kinin production (altered vascular permeability)

==Cloaca==
[[File:Endoderm_cartoon.jpg|File:Endoderm development]]
* hindgut region ending at the cloacal membrane
* divided (ventro-dorsally) by the urogenital septum
** ventral - common urogenital sinus
** dorsal - rectum

{| border='0px'

|-
| {{Renal overview movie}}
| {{Urogenital_septum_movie}}
|}

===Common urogenital sinus===
* superior end continuous with '''allantois'''
* common urogenital sinus and mesonephric duct fuse (connect)
* differentiates to form the bladder
* inferior end forms '''urethra'''
** this will be different in male and female development

===Urinary Bladder===
[[File:Adult_bladder.jpg‎|thumb|Adult bladder]]
* early origins of the bladder at the superior end of the common urogenital sinus
*8 open inferiorly to the cloaca and superiorly to the allantois
* Septation of the claoca - divides the anterior region to the primordial bladder component from the posterior rectal component.
* associated ureters and urethra

Dorsal view of developing bladder

[[Media:Trigone_3.mov|Trigone formation animation]]

* Ultrasound measurement of the bladder size can be used as a diagnostic tool for developmental abnormalities.

===Bladder Structure===
[[File:Bladder histology.jpg|thumb|Bladder histology]]
Can be described anatomically by its 4 layers from outside inward:
* Serous - the superior or abdominal surfaces and the lateral" surfaces of the bladder are covered by visceral peritoneum, the serous membrane (serosa) of the abdominal cavity, consisting of mesthelium and elastic fibrous connective tissue.
* Muscular - the detrusor muscle is the muscle of the urinary bladder wall.
* Submucosa - connects the muscular layer with the mucous layer.
* Mucosa - (mucus layer) a transitional epithelium layer formed into folds (rugae).

===Detrusor Muscle===
* The adult detrusor muscle consists of three layers of smooth (involuntary) muscle fibres.
** external layer - fibres arranged longitudinally
** middle layer - fibres arranged circularly
** internal layer - fibres arranged longitudinally

===Ureter Development===
* The adult ureter is a thick-walled muscular tube, 25 - 30 cm in length, running from the kidney to the urinary bladder.
* Anatomically can be described in two parts the abdominal part (pars abdominalis) and pelvic part (pars pelvina).
* The ureter is composed of three layers: outer fibrous layer (tunica adventitia), muscular layer (tunica muscularis) and mucous layer (tunica mucosa).
* The muscular layer can also be subdivided into 3 fibre layers: an external longitudinal, a middle circular, and an internal longitudinal.

===Urethra Development===
* Further development of the urinary system varies depending on the sex of the embryo.
* Males - the pelvic urethra forms the membranous urethra, the prostatic urethra and penile urethra. (The sex of the above animation and sections is male)
* Females - the pelvic urethra forms the membranous urethra and the vestibule of the vagina.

==Abnormalities==
[[File:Australian_abnormalities_pie_urogen.png|thumb]]
===Horseshoe Kidney===

{|
| [[File:Horseshoe kidney.jpg|400px]]
|
* fusion of the lower poles of the kidney.
* During migration from the sacral region the two metanephric blastemas can come into contact, mainly at the lower pole.
* The ureters pass in front of the zone of fusion of the kidneys.
* The kidneys and ureters usually function adequately but there is an increased incidence of upper urinary tract obstruction or infection.
* Some horseshoe variations have been described as having associated ureter abnormalities including duplications.
|}
===Kidney Vascular===
Supernumerary renal arteries

[[File:Accessory_renal_artery.jpg|300px]] [[File:Multiple_renal_arteries_01.jpg|300px]]

Supernumerary renal vein

[[File:Supernumerary_renal_vein_02.jpg|300px]] [[File:Supernumerary_renal_vein_04.jpg|300px]]

===Urorectal Septum Malformation===
* thought to be a deficiency in caudal mesoderm which in turn leads to the malformation of the urorectal septum and other structures in the pelvic region.
* Recent research has also identified the potential presence of a persistent urachus prior to septation of the cloaca (common urogenital sinus).

===Bladder===
* absent or small bladder -
associated with renal agenesis.

===Bladder Exstrophy===
[[File:Bladder_Exstrophy.jpg|thumb|Bladder_Exstrophy]]
* developmental abnormality associated with bladder development.
* origins appear to occur not just by abnormal bladder development, but by a congenital malformation of the ventral wall of abdomen (between umbilicus and pubic symphysis).
* There may also be other anomolies associated with failure of closure of abdominal wall and bladder (epispadias, pubic bone anomolies).

===Ureter and Urethra===
* Ureter - Duplex Ureter
* Urethra- Urethral Obstruction and Hypospadias

===Polycystic Kidney Disease===
[[File:Multicystic kidney.jpg|thumb|Multicystic kidney]]
* diffuse cystic malformation of both kidneys
* cystic malformations of liver and lung often associated, Often familial disposition
* Two types
** Infantile (inconsistent with prolonged survival)
** Adult (less severe and allows survival)
* Autosomal dominant PKD disease - recently identified at mutations in 2 different human genes encoding membrane proteins (possibly channels)

===Wilms' Tumor===
[[File:Wilms_tumor.jpg|thumb|Wilms' tumor]]
* (nephroblastoma) Named after Max Wilms, a German doctor who wrote first medical articles 1899
* most common type of kidney cancer children
* WT1 gene - encodes a zinc finger protein
* Both constitutional and somatic mutations disrupting the DNA-binding domain of WT1 result in a potentially dominant-negative phenotype
* some blastema cells (mass of undifferentiated cells) persist to form a ‘nephrogenic rest’
* Most rests become dormant or regress but others proliferate to form hyperplastic rests
* any type of rest can then undergo a genetic or epigenetic change to become a neoplastic rest
* can proliferate further to produce a benign lesion (adenomatous rest) or a malignant Wilms’ tumour

=== Prune Belly Syndrome ===
<gallery>
File:Hydronephrosis.jpg|
File:Renal_outflow_obstruction.jpg|
File:Prune_belly.jpg|Prune_belly
</gallery>
* lower urinary tract obstruction
* mainly male
* fetal urinary system ruptures leading to collapse and "prune belly" appearance.

==Additional Images==
<gallery>
File:Stage 11 historic-Atwell1930-3b.jpg|Stage 11 historic Atwell (1930)
File:Stage_11_historic-Heuser1930-1c.jpg|Stage 11 historic Heuser (1930)
File:Gray1128.jpg|Nephron structure
File:Nephron physiology.jpg|Nephron physiology
File:Gray1127.jpg|Kidney and adrenal gland (adult)
File:Endoderm cartoon.jpg|Endoderm cartoon
File:Fetal 10wk urogenital 1.jpg|Fetal urogenital region most lateral right
File:Fetal 10wk urogenital 2.jpg|Fetal urogenital region lateral right
File:Fetal 10wk urogenital 3.jpg|Fetal urogenital region medial
File:Fetal 10wk urogenital 4.jpg|Fetal urogenital region midline
File:Bladder_histology.jpg|Bladder histology
File:Australian_abnormalities_pie_urogen.png
File:Horseshoe kidney.jpg|Horseshoe kidney
File:Hydronephrosis.jpg|Hydronephrosis
File:Renal_outflow_obstruction.jpg‎|Renal outflow obstruction
File:Bladder Exstrophy.jpg‎|Bladder Exstrophy
</gallery>

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter 13 p303-346
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 10 p261-306
* '''Before We Are Born''' (5th ed.) Moore and Persaud Chapter14 p289-326
* '''Essentials of Human Embryology''', Larson Chapter 10 p173-205
* '''Human Embryology''', Fitzgerald and Fitzgerald Chapter 21-22 p134-152

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 Chapter 14 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.section.3498 Intermediate Mesoderm] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3498&rendertype=figure&id=A3500 Figure 14.18. General scheme of development in the vertebrate kidney] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6814 Figure 23-23. Mechanism of mesenchymal inductive effect on the ureteric bud] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3498&rendertype=figure&id=A3507 Figure 14.21. Ureteric bud growth is dependent on GDNF and its receptor]

* '''Molecular Cell Biology''' by Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. New York: W. H. Freeman & Co.; c1999 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6811 Reciprocal Epithelial-Mesenchymal Interactions Regulate Kidney Development] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6811 Figure 23-21. Embryonic development of the kidney]

===Reviews===
* Quaggin SE, Kreidberg JA. Development of the renal glomerulus: good neighbors and good fences. Development. 2008 Feb;135(4):609-20. [http://www.ncbi.nlm.nih.gov/pubmed/18184729 PMID: 18184729]
* Brenner-Anantharam A, Cebrian C, Guillaume R, Hurtado R, Sun TT, Herzlinger D. Tailbud-derived mesenchyme promotes urinary tract segmentation via BMP4 signaling. Development. 2007 May;134(10):1967-75. [http://www.ncbi.nlm.nih.gov/pubmed/17442697 PMID: 17442697]
* [http://www.nature.com/ng/meetings/nephrogenetics/index.html Forefronts Symposium on Nephrogenetics: from development to physiology March 8-11, 2007 Danvers, MA] A meeting to synthesize an integrated view of the normal development and function of the kidney from the genetic standpoint.
* Costantini F. Renal branching morphogenesis: concepts, questions, and recent advances. Differentiation. 2006 Sep;74(7):402-21. [http://www.ncbi.nlm.nih.gov/pubmed/16916378 PMID: 16916378]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=intermediate_mesoderm intermediate mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=kidney_development kidney development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=renal_development renal development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=ureteric+bud ureteric bud] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=nephron_development nephron development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=bladder+development bladder development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=intermediate_mesoderm intermediate mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=kidney_development kidney development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=renal_development renal development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=ureteric_bud ureteric bud] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=nephron_development nephron development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=bladder+development bladder development]

== Terms ==
* '''bladder exstrophy''' - A congenital malformation with bladder open to ventral wall of abdomen (between umbilicus and pubic symphysis) and may have other anomolies associated with failure of closure of abdominal wall and bladder (epispadias, pubic bone anomolies).
* '''blastema''' - Term used to describe a mass of undifferentiated cells.
* '''diabetes insipidus''' - The disorder is related to the hormone antidiuretic hormone (ADH, also called vasopressin) its synthesis, secretion, receptors and signaling pathway. In diabetes insipidus there is an excretion of large amounts (up to 30 litres/day) of a watery urine and an unremitting thirst.
* '''hydronephrosis''' - (congenital hydronephrosis, Greek, ''hydro'' = water) A kidney abnormality due to partial or complete obstruction at the pelvi-ureteric junction. This leads to a grossly dilated renal pelvis causing extensive renal damage before birth.
* '''hyperplastic rests''' - In kidney development, embryonic blastema cells can persist and proliferate to form a pool of cells, which under either genetic or epigenetic influence can then change to become a neoplastic rest. Normally the majority of nephrogenic rests either regress or become dormant.
* '''mesonephros''' - The second temporary stage of kidney development (pro-, meso-, meta-). The intermediate mesonephros develops and disappears with the exception of its duct, the '''mesonephric duct''', which will form the male reproductive duct system. In males, the mesonephric tubules go on to form the ducts of the testis. In females, these degenerate. A few mesonephric tubules remain as efferent ductules in the male and vestigial remnants in the female.
* '''mesonephric duct''' - (= Wollfian duct) An early developing urogenital duct running the length of the embryo that will differentiate and form the male reproductive duct system. In females this duct degenerates (some remnants may remain associated in broad ligament).
* '''metanephros''' - The adult kidney, third stage of mammalian kidney (pro-, meso-, '''meta-''') development within the intermediate mesoderm.
* '''metanephric cap''' - In kidney development, the intermediate mesoderm which surrounds the ureteric bud and will develop into nephrons.
* '''multicystic kidney''' - There is no functional kidney tissue present in the kidney and it is replaced by a multilocular cyst. This is non-familial and is produced by atresia of a ureter and is always unilateral.
* '''neoplastic rest''' - In kidney development, a neoplastic rest can develop under either genetic or epigenetic influence from a hyperplastic rest, originating from an embryonic blastema cell. Normally the majority of nephrogenic rests either regress or become dormant.
* '''nephrogenic rest''' - A kidney term used to describe the embryonic blastema cells which persist and under either genetic or epigenetic can change to become a neoplastic rest. These neoplastic rests can develop postnatally as a benign form (adenomatous rest) or a malignant [W.htm#Wilms_tumour Wilm's tumour] form. The rests are further characterised by the time of generation leading to different anatomical kidney locations: early intralobar nephrogenic rests (within the renal lobe) and late pelilobar nephrogenic rests (periphery of the renal lobe).
* '''nephron''' - (Greek, ''nephros'' = kidney) The functional unit of the kidney.
* '''nephros''' - (Greek, ''nephros'' = kidney) Term used to describe features associated with the kidney. (pronephros, mesonephros, metanephros, nephric, nephron, nephroblastoma).
* '''podocyte''' - (visceral epithelial cell) kidney glomerulus cell forming the main component of the glomerular filtration barrier.
* '''podocyte specific proteins''' - podocalyxin, glomerular epithelial protein-1, podocin, nephrin, synaptopodin, and alpha-actinin-4), podocyte synthesized proteins (vascular endothelial growth factor and novH), transcription factors (WT1 and PAX2).
* '''pronephros''' - (Greek, ''pro'' = before) The first temporary stage of kidney development (pro-, meso-, meta-). This forms the kidney of primitive fish and lower vertebrates. Kidney development occurs within the intermediate mesoderm interacting with endoderm. In humans, this very rudimentary kidney forms very early at the level of the neck. It is rapidly replaced by the mesonephros, intermediate stage kidney, differentiating in mesoderm beneath.
* '''proteinuria''' - The abnormal presence of protein in the urine and an indicator of diesease including diabetic kidney disease (DKD, diabetic nephropathy).
* '''renal''' - (Latin, ''renes'' = kidney) Term used in relation to the kidney and associated structures (renal pelvis, renal artery)
* '''ureter''' - The two ureters are hollow tubes that link and carries urine from kidney to the bladder. The tubes have a muscular wall lined with transitional epithelium.
* '''urethra''' - The single muscular tube that links and carries urine from the bladder to the exterior. In humans, the urethral length differs between the sexes (male longer, female shorter).
* '''urinary''' - Term used to describe all components of the kidney system including the bladder, ureters and urethra.
* '''urine''' - Term used to describe the liquid waste produced by the kidney, stored in the bladder and excreted from teh body through the urethra.
* '''urorectal septum''' - (URS) The structure which develops to separate the cloaca (common urogenital sinus) into an anterior urinary part and a posterior rectal part.
* '''Wilms' tumour''' - A form of kidney/renal cancer (nephroblastoma) named after Dr Max Wilms who first described the tumor. This childhood kidney cancer is caused by the inactivation of a tumour suppressor gene (BRCA2) or Wilms tumor-1 gene (Wt1) and is one of the most common solid tumors of childhood, occurring in 1 in 10,000 children and accounting for 8% of childhood cancers. Wt1 also required at early stages of gonadal development. (More? [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=194070 OMIM - Wilm's tumour] | [http://www.whonamedit.com/doctor.cfm/2109.html Dr Max Wilms])
* '''Wilms' tumor 1-associating protein''' - (WTAP) protein expressed in extraembryonic tissues and required for the formation of embryonic mesoderm and endoderm.
* '''Wolffian duct''' - (= mesonephric duct, preferred terminology), runs from the mesonephros to cloaca, differentiates to form the male vas deferens and in the female regresses. Named after Caspar Friedrich Wolff (1733-1794), a German scientist and early embryology researcher and is said to have established the doctrine of germ layers. (More? [http://www.whonamedit.com/doctor.cfm/2433.html Caspar Friedrich Wolff])

----

{{2012ANAT2341}}

----

[[Category:Renal]]

Lecture - Renal Development

2013-09-23T02:26:26Z

Z3283213: Undo revision 125206 by Z3283213 (talk)

==Introduction==
[[File:Gray1127.jpg|thumb|Historic drawing of adult kidney]]
{|
| width=380px|<mediaplayer width='360' height='500' image="http://embryology.med.unsw.edu.au/embryology/images/f/fe/Urogenital_sinus_001_icon.jpg">File:Urogenital_sinus_001.mp4</mediaplayer>

[[Urogenital Sinus Movie]]
|
'''Urogenital Sinus and Renal Development'''

This animation gives an overview of both early renal and genital (urogenital) development associated with the urogenital sinus.

The paired adult kidneys filter blood, excrete waste, reabsorb water and have endocrine functions. In the embryo, there are several stages in their development closely linked to genital development. The nephron, the functional unit of the kidney, is also a classical epithelial/mesenchyme type of interaction.

The urinary system is developmentally and anatomically associated with genital development, often described as the urogenital system.

{{Renal overview movie}}

|}

{|
| [[File:Podcast_icon.jpg|link=ANAT2341_Embryology_2012_Lecture_Recordings]]
| '''Lectopia Lecture Audio'''

[http://lectopia.telt.unsw.edu.au/lectopia/lectopia.lasso?ut=153&id=140236 Lecture 15 - Renal Development]

Lecture Date: 2012-09-18 Lecture Time: 11:00 Venue: BioMed E Speaker: Mark Hill

|}

==Objectives ==
[[File:Stage 13 kidney sections.jpg|right]]
* Understand the 3 main stages of kidney development.
* Understand development of the nephron and renal papilla.
* Brief understanding of the mechanisms of nephron development.
* Understand the development of the cloaca, ureter and bladder.
* Brief understanding of abnormalities of the urinary system.

{|
| [[File:Podcast_icon.jpg|link=ANAT2341_Embryology_2011_Lecture_Recordings]]
| '''Lectopia Lecture Audio'''

|}

==Textbooks==
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| '''Citation:''' UNSW Embryology 12th ed. Hill, M.A. Sydney, UNSW 2012

{{Renal Links}} | [[2010_Lecture_15|2010 Lecture]]
|}

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00012-6 Chapter 12 - Urogenital System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10015-6 Chapter 15 - Development of the Urogenital System]
|}

:'''Links:''' [[Embryology Textbooks]]

== Background==
* Mesoderm then intermediate mesoderm
* Vascular Development
* Gastrointestional
* Cloacal development
* Endocrine - covered in future lecture/lab

==Movies==

{{Renal cartoons}}

==Renal Anatomy==
[[File:Nephron histology.jpg|thumb|Nephron histology]]
{|
| '''Kidney'''
* Nephron - Functional unit of kidney
* Humans up to 1 million
* Filtration of waste from blood
* Endocrine
* Blood pressure regulation
| '''Ureter'''
* Urine transport to bladder
'''Urinary Bladder'''
* Urine storage
'''Urethra'''
* Urine transport to bladder
|
Germ layers
* Endoderm - lining bladder also lines allantois
* Mesoderm - Intermediate mesoderm (lies between somites and lateral plate)
* Ectoderm - innervation
|}

==Intermediate Mesoderm==
[[File:Stage7_intermediate-mesoderm.jpg|thumb|Week 3 intermediate mesoderm]]
* development occurs laterally symmetrical (left right)
* intermediate mesoderm lying beside the '''dorsal aorta'''
* initially form '''mesonephric tubules''' (epithelial)
* these tubules connect to a common duct, '''mesonephric duct'''
* the mesonephric duct then extends within the mesoderm, rostro-caudally
* eventually making contact with the '''cloaca'''

==Mesonephric Duct==

Later in development, both the mesonephric duct and the cloaca both continue to differentiate and undergo extensive remodelling (and renaming)

===Uteric Bud===

* arise near the cloacal connection of the mesonephric duct
* branch from the mesonephric duct laterally into the intermediate mesoderm
* induce the surrounding mesoderm to differentiate - metanephric blastema
** this mesoderm will in turn signal back to differentiate the uteric bud

'''Epithelial - mesenchymal interaction'''

Uteric Bud forms - ureter, pelvis, calyces, collecting ducts

===Metanephric Blastema===

* forms glomeruli, capsule, nephron tubules
* this development continues through fetal period

==Nephros Development==
The 3 main stages and pairs during development:

# pronephros
# mesonephros
# metanephros

===Pronephros===
* week 4 few cells in cervical region fish
* Human E18, Mouse E7.5 - pronephric duct forms first with associated nephrogenic mesenchyme
* grows rostro caudally cervical -> cloaca
* E22 nephrogenic mesenchyme differentiates to form pronephroi not functional in mammals degenerates rapidly

===Mesonephros===
[[File:Stage 13 kidney sections 2.jpg|thumb|Stage 13 mesonephros]]
[[File:Stage22 mesonephros.jpg|thumb|Stage 22 mesonephros]]
* Human E24, Mouse E9.5 caudal to pronephros
* forms by induction from pronephros
* pronephric duct now becomes mesonephric duct (also called Wolffian Duct)

===Metanephros===
* Human E35-37, Mouse E11 epithelia bud at end of mesonephric duct uteric bud and associated metanephric mesenchyme
{|
| {{Urogenital stage 22 movie}}
| {{Gastrointestinal stage 13 movie}}
|}

===Uteric Bud===
* induced by metanephric mesenchyme to differentiate
* forms collecting tubules, renal pelvis, ureter
* metanephric mesenchyme induced by uteric to differentiate forms nephron

===Week 5 and Week 8===
{|

| [[File:Stage 13 image 081.jpg|400px]]
| [[File:Stage_22_image_188.jpg|400px]]
|-
| Embryo Stage 13 mesonephros (week 5)
| Embryo Stage 22 metanephros (week 8)
|}

[[File:Stage_22_image_189.jpg|400px]]

===Fetal===
[[File:Fetal_10wk_urogenital_1.jpg|thumb|early fetal kidney]]

<gallery>
File:Human_fetal_kidney_histology_01.jpg
File:Human_fetal_kidney_histology_02.jpg
File:Human_fetal_kidney_histology_03.jpg
File:Human_fetal_kidney_histology_04.jpg
</gallery>

== Nephron ==
[[File:Gray1128.jpg|thumb|Adult nephron structure]]
[[File:Nephron histology.jpg|thumb|Nephron histology]]

{| border='0px'
|-
{{Nephron movie}}
| valign="top" |'''Early Renal Development'''

'''Legend'''

* '''Uteric Bud''' - developing ureter, pelvis, calyces, collecting ducts
* '''Metanephric Blastema''' (intermediate mesoderm) - developing glomeruli, capsule, nephron tubules

Development has four developmental stages:
# '''vesicle''' (V) stage (13-19 weeks)
# '''S-shaped body''' (S) stage ( 20-24 weeks)
# '''capillary loop''' (C) stage (25-29 weeks)
# '''maturation''' (M) stage (infants aged 1-6 months)

'''Links:''' [[Quicktime Development Animation - Renal|Quicktime version]] | [[Development Animation - Urogenital Sinus|Animation - Urogenital Sinus]] | [[Renal System Development]]
|-
|}

===Nephron Development===
* disorganised mesenchymal cells become a highly organised epithelial tubule
* Condensation - groups of about 100 cells condense tightly together to form a distinct mass
* Epithelialisation - condensed cells lose their mesenchymal character and gain epithelial
* At end of this period formed a small epithelial cyst complete with a basement membrane, cell-cell junctions and a defined cellular apico-basal polarity.

===Early morphogenesis===
[[File:Renal - podocyte development 01.jpg|thumb|Renal - podocyte development]]
* cyst invaginates twice to form a comma
* then a S-shaped body one invagination site later becomes the glomerular cleft
* At about this time blood vessel progenitors invade cleft to begin construction of vascular component of glomerulus
* Tubule maturation specialised transporting segments of nephron differentiate complex of convoluted tubules is created

[[File:Glomerular podocyte cartoon.jpg|500px]]

===Adult nephron structure===
* mean glomerular number shown to level at 36 weeks
** about 15,000 at 15 weeks
** about 740,000 at 40 weeks.

* key structure of the adult nephron is the glomerulus (renal corpuscle), which represents the vascular/renal interface.

<gallery>
File:Nephron_histology_01.jpg|Glomerulus structure
File:Nephron_histology_02.jpg|Vascular and renal poles
</gallery>

'''Related Images:''' [[:File:Nephron_histology.jpg|Nephron histology overview]] | [[:File:Nephron_histology 01.jpg|glomerulus structure]] | [[:File:Nephron_histology 02.jpg|vascular and renal poles]]

==Renal Vascular==
===Renal Arteries===
{|
| {{Renal vascular movie}}
|
* starts in week 5 and is completed by week 15.
* week 6 - the kidneys begin to change their relative position, described as "ascent of the kidneys", to their correct anatomical position.
* week 9 - the rising movement is completed.
* During the ascent, the kidneys also become vascularised via the dorsal aorta.
* As this ascent occurs, the mesonephric ducts and the ureters enter the wall of the developing bladder.
|}
* Arise with ascent and inferior branches lost
* Sequential, 25% population have 2 or more renal arteries
* branch of abdominal aorta, divides into 4-5 branches
** each gives off small branches to suprarenal glands, ureter, surrounding cellular tissue and muscles
* Frequently a second renal artery (inferior renal) from abdominal aorta at a lower level, supplies lower portion of kidney.

===Renal Venous===
{|
| [[File:Embryo_renal_venous_cartoon.jpg|300px]]
| [[File:Adult_renal_venous_cartoon.jpg|300px]]
|-
| Embryo renal venous
| Adult renal venous
|}

==Endocrine Kidney==
Covered also in Endocrine Development lecture
* Renin - Increase Angiotensin-aldosterone system
* Prostaglandins - decrease Na+ reabsorption
* Erythropoietin - Increase Erythrocyte (rbc) production
* 1,25 (OH)2 vitamin D - Calcium homeostasis
* Prekallikreins - (plasma protein inactive precursor of kallikrein) Increase kinin production (altered vascular permeability)

==Cloaca==
[[File:Endoderm_cartoon.jpg|File:Endoderm development]]
* hindgut region ending at the cloacal membrane
* divided (ventro-dorsally) by the urogenital septum
** ventral - common urogenital sinus
** dorsal - rectum

{| border='0px'

|-
| {{Renal overview movie}}
| {{Urogenital_septum_movie}}
|}

===Common urogenital sinus===
* superior end continuous with '''allantois'''
* common urogenital sinus and mesonephric duct fuse (connect)
* differentiates to form the bladder
* inferior end forms '''urethra'''
** this will be different in male and female development

===Urinary Bladder===
[[File:Adult_bladder.jpg‎|thumb|Adult bladder]]
* early origins of the bladder at the superior end of the common urogenital sinus
*8 open inferiorly to the cloaca and superiorly to the allantois
* Septation of the claoca - divides the anterior region to the primordial bladder component from the posterior rectal component.
* associated ureters and urethra

Dorsal view of developing bladder

[[Media:Trigone_3.mov|Trigone formation animation]]

* Ultrasound measurement of the bladder size can be used as a diagnostic tool for developmental abnormalities.

===Bladder Structure===
[[File:Bladder histology.jpg|thumb|Bladder histology]]
Can be described anatomically by its 4 layers from outside inward:
* Serous - the superior or abdominal surfaces and the lateral" surfaces of the bladder are covered by visceral peritoneum, the serous membrane (serosa) of the abdominal cavity, consisting of mesthelium and elastic fibrous connective tissue.
* Muscular - the detrusor muscle is the muscle of the urinary bladder wall.
* Submucosa - connects the muscular layer with the mucous layer.
* Mucosa - (mucus layer) a transitional epithelium layer formed into folds (rugae).

===Detrusor Muscle===
* The adult detrusor muscle consists of three layers of smooth (involuntary) muscle fibres.
** external layer - fibres arranged longitudinally
** middle layer - fibres arranged circularly
** internal layer - fibres arranged longitudinally

===Ureter Development===
* The adult ureter is a thick-walled muscular tube, 25 - 30 cm in length, running from the kidney to the urinary bladder.
* Anatomically can be described in two parts the abdominal part (pars abdominalis) and pelvic part (pars pelvina).
* The ureter is composed of three layers: outer fibrous layer (tunica adventitia), muscular layer (tunica muscularis) and mucous layer (tunica mucosa).
* The muscular layer can also be subdivided into 3 fibre layers: an external longitudinal, a middle circular, and an internal longitudinal.

===Urethra Development===
* Further development of the urinary system varies depending on the sex of the embryo.
* Males - the pelvic urethra forms the membranous urethra, the prostatic urethra and penile urethra. (The sex of the above animation and sections is male)
* Females - the pelvic urethra forms the membranous urethra and the vestibule of the vagina.

==Abnormalities==
[[File:Australian_abnormalities_pie_urogen.png|thumb]]
===Horseshoe Kidney===

{|
| [[File:Horseshoe kidney.jpg|400px]]
|
* fusion of the lower poles of the kidney.
* During migration from the sacral region the two metanephric blastemas can come into contact, mainly at the lower pole.
* The ureters pass in front of the zone of fusion of the kidneys.
* The kidneys and ureters usually function adequately but there is an increased incidence of upper urinary tract obstruction or infection.
* Some horseshoe variations have been described as having associated ureter abnormalities including duplications.
|}
===Kidney Vascular===
Supernumerary renal arteries

[[File:Accessory_renal_artery.jpg|300px]] [[File:Multiple_renal_arteries_01.jpg|300px]]

Supernumerary renal vein

[[File:Supernumerary_renal_vein_02.jpg|300px]] [[File:Supernumerary_renal_vein_04.jpg|300px]]

===Urorectal Septum Malformation===
* thought to be a deficiency in caudal mesoderm which in turn leads to the malformation of the urorectal septum and other structures in the pelvic region.
* Recent research has also identified the potential presence of a persistent urachus prior to septation of the cloaca (common urogenital sinus).

===Bladder===
* absent or small bladder -
associated with renal agenesis.

===Bladder Exstrophy===
[[File:Bladder_Exstrophy.jpg|thumb|Bladder_Exstrophy]]
* developmental abnormality associated with bladder development.
* origins appear to occur not just by abnormal bladder development, but by a congenital malformation of the ventral wall of abdomen (between umbilicus and pubic symphysis).
* There may also be other anomolies associated with failure of closure of abdominal wall and bladder (epispadias, pubic bone anomolies).

===Ureter and Urethra===
* Ureter - Duplex Ureter
* Urethra- Urethral Obstruction and Hypospadias

===Polycystic Kidney Disease===
[[File:Multicystic kidney.jpg|thumb|Multicystic kidney]]
* diffuse cystic malformation of both kidneys
* cystic malformations of liver and lung often associated, Often familial disposition
* Two types
** Infantile (inconsistent with prolonged survival)
** Adult (less severe and allows survival)
* Autosomal dominant PKD disease - recently identified at mutations in 2 different human genes encoding membrane proteins (possibly channels)

===Wilms' Tumor===
[[File:Wilms_tumor.jpg|thumb|Wilms' tumor]]
* (nephroblastoma) Named after Max Wilms, a German doctor who wrote first medical articles 1899
* most common type of kidney cancer children
* WT1 gene - encodes a zinc finger protein
* Both constitutional and somatic mutations disrupting the DNA-binding domain of WT1 result in a potentially dominant-negative phenotype
* some blastema cells (mass of undifferentiated cells) persist to form a ‘nephrogenic rest’
* Most rests become dormant or regress but others proliferate to form hyperplastic rests
* any type of rest can then undergo a genetic or epigenetic change to become a neoplastic rest
* can proliferate further to produce a benign lesion (adenomatous rest) or a malignant Wilms’ tumour

=== Prune Belly Syndrome ===
<gallery>
File:Hydronephrosis.jpg|
File:Renal_outflow_obstruction.jpg|
File:Prune_belly.jpg|Prune_belly
</gallery>
* lower urinary tract obstruction
* mainly male
* fetal urinary system ruptures leading to collapse and "prune belly" appearance.

==Additional Images==
<gallery>
File:Stage 11 historic-Atwell1930-3b.jpg|Stage 11 historic Atwell (1930)
File:Stage_11_historic-Heuser1930-1c.jpg|Stage 11 historic Heuser (1930)
File:Gray1128.jpg|Nephron structure
File:Nephron physiology.jpg|Nephron physiology
File:Gray1127.jpg|Kidney and adrenal gland (adult)
File:Endoderm cartoon.jpg|Endoderm cartoon
File:Fetal 10wk urogenital 1.jpg|Fetal urogenital region most lateral right
File:Fetal 10wk urogenital 2.jpg|Fetal urogenital region lateral right
File:Fetal 10wk urogenital 3.jpg|Fetal urogenital region medial
File:Fetal 10wk urogenital 4.jpg|Fetal urogenital region midline
File:Bladder_histology.jpg|Bladder histology
File:Australian_abnormalities_pie_urogen.png
File:Horseshoe kidney.jpg|Horseshoe kidney
File:Hydronephrosis.jpg|Hydronephrosis
File:Renal_outflow_obstruction.jpg‎|Renal outflow obstruction
File:Bladder Exstrophy.jpg‎|Bladder Exstrophy
</gallery>

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter 13 p303-346
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 10 p261-306
* '''Before We Are Born''' (5th ed.) Moore and Persaud Chapter14 p289-326
* '''Essentials of Human Embryology''', Larson Chapter 10 p173-205
* '''Human Embryology''', Fitzgerald and Fitzgerald Chapter 21-22 p134-152

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 Chapter 14 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.section.3498 Intermediate Mesoderm] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3498&rendertype=figure&id=A3500 Figure 14.18. General scheme of development in the vertebrate kidney] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6814 Figure 23-23. Mechanism of mesenchymal inductive effect on the ureteric bud] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3498&rendertype=figure&id=A3507 Figure 14.21. Ureteric bud growth is dependent on GDNF and its receptor]

* '''Molecular Cell Biology''' by Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. New York: W. H. Freeman & Co.; c1999 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6811 Reciprocal Epithelial-Mesenchymal Interactions Regulate Kidney Development] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6811 Figure 23-21. Embryonic development of the kidney]

===Reviews===
* Quaggin SE, Kreidberg JA. Development of the renal glomerulus: good neighbors and good fences. Development. 2008 Feb;135(4):609-20. [http://www.ncbi.nlm.nih.gov/pubmed/18184729 PMID: 18184729]
* Brenner-Anantharam A, Cebrian C, Guillaume R, Hurtado R, Sun TT, Herzlinger D. Tailbud-derived mesenchyme promotes urinary tract segmentation via BMP4 signaling. Development. 2007 May;134(10):1967-75. [http://www.ncbi.nlm.nih.gov/pubmed/17442697 PMID: 17442697]
* [http://www.nature.com/ng/meetings/nephrogenetics/index.html Forefronts Symposium on Nephrogenetics: from development to physiology March 8-11, 2007 Danvers, MA] A meeting to synthesize an integrated view of the normal development and function of the kidney from the genetic standpoint.
* Costantini F. Renal branching morphogenesis: concepts, questions, and recent advances. Differentiation. 2006 Sep;74(7):402-21. [http://www.ncbi.nlm.nih.gov/pubmed/16916378 PMID: 16916378]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=intermediate_mesoderm intermediate mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=kidney_development kidney development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=renal_development renal development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=ureteric+bud ureteric bud] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=nephron_development nephron development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=bladder+development bladder development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=intermediate_mesoderm intermediate mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=kidney_development kidney development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=renal_development renal development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=ureteric_bud ureteric bud] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=nephron_development nephron development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=bladder+development bladder development]

== Terms ==
* '''bladder exstrophy''' - A congenital malformation with bladder open to ventral wall of abdomen (between umbilicus and pubic symphysis) and may have other anomolies associated with failure of closure of abdominal wall and bladder (epispadias, pubic bone anomolies).
* '''blastema''' - Term used to describe a mass of undifferentiated cells.
* '''diabetes insipidus''' - The disorder is related to the hormone antidiuretic hormone (ADH, also called vasopressin) its synthesis, secretion, receptors and signaling pathway. In diabetes insipidus there is an excretion of large amounts (up to 30 litres/day) of a watery urine and an unremitting thirst.
* '''hydronephrosis''' - (congenital hydronephrosis, Greek, ''hydro'' = water) A kidney abnormality due to partial or complete obstruction at the pelvi-ureteric junction. This leads to a grossly dilated renal pelvis causing extensive renal damage before birth.
* '''hyperplastic rests''' - In kidney development, embryonic blastema cells can persist and proliferate to form a pool of cells, which under either genetic or epigenetic influence can then change to become a neoplastic rest. Normally the majority of nephrogenic rests either regress or become dormant.
* '''mesonephros''' - The second temporary stage of kidney development (pro-, meso-, meta-). The intermediate mesonephros develops and disappears with the exception of its duct, the '''mesonephric duct''', which will form the male reproductive duct system. In males, the mesonephric tubules go on to form the ducts of the testis. In females, these degenerate. A few mesonephric tubules remain as efferent ductules in the male and vestigial remnants in the female.
* '''mesonephric duct''' - (= Wollfian duct) An early developing urogenital duct running the length of the embryo that will differentiate and form the male reproductive duct system. In females this duct degenerates (some remnants may remain associated in broad ligament).
* '''metanephros''' - The adult kidney, third stage of mammalian kidney (pro-, meso-, '''meta-''') development within the intermediate mesoderm.
* '''metanephric cap''' - In kidney development, the intermediate mesoderm which surrounds the ureteric bud and will develop into nephrons.
* '''multicystic kidney''' - There is no functional kidney tissue present in the kidney and it is replaced by a multilocular cyst. This is non-familial and is produced by atresia of a ureter and is always unilateral.
* '''neoplastic rest''' - In kidney development, a neoplastic rest can develop under either genetic or epigenetic influence from a hyperplastic rest, originating from an embryonic blastema cell. Normally the majority of nephrogenic rests either regress or become dormant.
* '''nephrogenic rest''' - A kidney term used to describe the embryonic blastema cells which persist and under either genetic or epigenetic can change to become a neoplastic rest. These neoplastic rests can develop postnatally as a benign form (adenomatous rest) or a malignant [W.htm#Wilms_tumour Wilm's tumour] form. The rests are further characterised by the time of generation leading to different anatomical kidney locations: early intralobar nephrogenic rests (within the renal lobe) and late pelilobar nephrogenic rests (periphery of the renal lobe).
* '''nephron''' - (Greek, ''nephros'' = kidney) The functional unit of the kidney.
* '''nephros''' - (Greek, ''nephros'' = kidney) Term used to describe features associated with the kidney. (pronephros, mesonephros, metanephros, nephric, nephron, nephroblastoma).
* '''podocyte''' - (visceral epithelial cell) kidney glomerulus cell forming the main component of the glomerular filtration barrier.
* '''podocyte specific proteins''' - podocalyxin, glomerular epithelial protein-1, podocin, nephrin, synaptopodin, and alpha-actinin-4), podocyte synthesized proteins (vascular endothelial growth factor and novH), transcription factors (WT1 and PAX2).
* '''pronephros''' - (Greek, ''pro'' = before) The first temporary stage of kidney development (pro-, meso-, meta-). This forms the kidney of primitive fish and lower vertebrates. Kidney development occurs within the intermediate mesoderm interacting with endoderm. In humans, this very rudimentary kidney forms very early at the level of the neck. It is rapidly replaced by the mesonephros, intermediate stage kidney, differentiating in mesoderm beneath.
* '''proteinuria''' - The abnormal presence of protein in the urine and an indicator of diesease including diabetic kidney disease (DKD, diabetic nephropathy).
* '''renal''' - (Latin, ''renes'' = kidney) Term used in relation to the kidney and associated structures (renal pelvis, renal artery)
* '''ureter''' - The two ureters are hollow tubes that link and carries urine from kidney to the bladder. The tubes have a muscular wall lined with transitional epithelium.
* '''urethra''' - The single muscular tube that links and carries urine from the bladder to the exterior. In humans, the urethral length differs between the sexes (male longer, female shorter).
* '''urinary''' - Term used to describe all components of the kidney system including the bladder, ureters and urethra.
* '''urine''' - Term used to describe the liquid waste produced by the kidney, stored in the bladder and excreted from teh body through the urethra.
* '''urorectal septum''' - (URS) The structure which develops to separate the cloaca (common urogenital sinus) into an anterior urinary part and a posterior rectal part.
* '''Wilms' tumour''' - A form of kidney/renal cancer (nephroblastoma) named after Dr Max Wilms who first described the tumor. This childhood kidney cancer is caused by the inactivation of a tumour suppressor gene (BRCA2) or Wilms tumor-1 gene (Wt1) and is one of the most common solid tumors of childhood, occurring in 1 in 10,000 children and accounting for 8% of childhood cancers. Wt1 also required at early stages of gonadal development. (More? [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=194070 OMIM - Wilm's tumour] | [http://www.whonamedit.com/doctor.cfm/2109.html Dr Max Wilms])
* '''Wilms' tumor 1-associating protein''' - (WTAP) protein expressed in extraembryonic tissues and required for the formation of embryonic mesoderm and endoderm.
* '''Wolffian duct''' - (= mesonephric duct, preferred terminology), runs from the mesonephros to cloaca, differentiates to form the male vas deferens and in the female regresses. Named after Caspar Friedrich Wolff (1733-1794), a German scientist and early embryology researcher and is said to have established the doctrine of germ layers. (More? [http://www.whonamedit.com/doctor.cfm/2433.html Caspar Friedrich Wolff])

----

{{2012ANAT2341}}

----

[[Category:Renal]]

File:Renal.pdf

2013-09-23T02:24:31Z

Z3283213:

Lecture - Renal Development

2013-09-23T02:23:53Z

Z3283213:

==Introduction==
[[File:Gray1127.jpg|thumb|Historic drawing of adult kidney]]
{|
| width=380px|<mediaplayer width='360' height='500' image="http://embryology.med.unsw.edu.au/embryology/images/f/fe/Urogenital_sinus_001_icon.jpg">File:Urogenital_sinus_001.mp4</mediaplayer>

[[Urogenital Sinus Movie]]
|
'''Urogenital Sinus and Renal Development'''

This animation gives an overview of both early renal and genital (urogenital) development associated with the urogenital sinus.

The paired adult kidneys filter blood, excrete waste, reabsorb water and have endocrine functions. In the embryo, there are several stages in their development closely linked to genital development. The nephron, the functional unit of the kidney, is also a classical epithelial/mesenchyme type of interaction.

The urinary system is developmentally and anatomically associated with genital development, often described as the urogenital system.

{{Renal overview movie}}

==Objectives ==
[[File:Stage 13 kidney sections.jpg|right]]
* Understand the 3 main stages of kidney development.
* Understand development of the nephron and renal papilla.
* Brief understanding of the mechanisms of nephron development.
* Understand the development of the cloaca, ureter and bladder.
* Brief understanding of abnormalities of the urinary system.

Lecture Date: 2013-09-24 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Renal.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

==Textbooks==
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| '''Citation:''' UNSW Embryology 12th ed. Hill, M.A. Sydney, UNSW 2012

{{Renal Links}} | [[2010_Lecture_15|2010 Lecture]]
|}

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00012-6 Chapter 12 - Urogenital System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10015-6 Chapter 15 - Development of the Urogenital System]
|}

:'''Links:''' [[Embryology Textbooks]]

== Background==
* Mesoderm then intermediate mesoderm
* Vascular Development
* Gastrointestional
* Cloacal development
* Endocrine - covered in future lecture/lab

==Movies==

{{Renal cartoons}}

==Renal Anatomy==
[[File:Nephron histology.jpg|thumb|Nephron histology]]
{|
| '''Kidney'''
* Nephron - Functional unit of kidney
* Humans up to 1 million
* Filtration of waste from blood
* Endocrine
* Blood pressure regulation
| '''Ureter'''
* Urine transport to bladder
'''Urinary Bladder'''
* Urine storage
'''Urethra'''
* Urine transport to bladder
|
Germ layers
* Endoderm - lining bladder also lines allantois
* Mesoderm - Intermediate mesoderm (lies between somites and lateral plate)
* Ectoderm - innervation
|}

==Intermediate Mesoderm==
[[File:Stage7_intermediate-mesoderm.jpg|thumb|Week 3 intermediate mesoderm]]
* development occurs laterally symmetrical (left right)
* intermediate mesoderm lying beside the '''dorsal aorta'''
* initially form '''mesonephric tubules''' (epithelial)
* these tubules connect to a common duct, '''mesonephric duct'''
* the mesonephric duct then extends within the mesoderm, rostro-caudally
* eventually making contact with the '''cloaca'''

==Mesonephric Duct==

Later in development, both the mesonephric duct and the cloaca both continue to differentiate and undergo extensive remodelling (and renaming)

===Uteric Bud===

* arise near the cloacal connection of the mesonephric duct
* branch from the mesonephric duct laterally into the intermediate mesoderm
* induce the surrounding mesoderm to differentiate - metanephric blastema
** this mesoderm will in turn signal back to differentiate the uteric bud

'''Epithelial - mesenchymal interaction'''

Uteric Bud forms - ureter, pelvis, calyces, collecting ducts

===Metanephric Blastema===

* forms glomeruli, capsule, nephron tubules
* this development continues through fetal period

==Nephros Development==
The 3 main stages and pairs during development:

# pronephros
# mesonephros
# metanephros

===Pronephros===
* week 4 few cells in cervical region fish
* Human E18, Mouse E7.5 - pronephric duct forms first with associated nephrogenic mesenchyme
* grows rostro caudally cervical -> cloaca
* E22 nephrogenic mesenchyme differentiates to form pronephroi not functional in mammals degenerates rapidly

===Mesonephros===
[[File:Stage 13 kidney sections 2.jpg|thumb|Stage 13 mesonephros]]
[[File:Stage22 mesonephros.jpg|thumb|Stage 22 mesonephros]]
* Human E24, Mouse E9.5 caudal to pronephros
* forms by induction from pronephros
* pronephric duct now becomes mesonephric duct (also called Wolffian Duct)

===Metanephros===
* Human E35-37, Mouse E11 epithelia bud at end of mesonephric duct uteric bud and associated metanephric mesenchyme
{|
| {{Urogenital stage 22 movie}}
| {{Gastrointestinal stage 13 movie}}
|}

===Uteric Bud===
* induced by metanephric mesenchyme to differentiate
* forms collecting tubules, renal pelvis, ureter
* metanephric mesenchyme induced by uteric to differentiate forms nephron

===Week 5 and Week 8===
{|

| [[File:Stage 13 image 081.jpg|400px]]
| [[File:Stage_22_image_188.jpg|400px]]
|-
| Embryo Stage 13 mesonephros (week 5)
| Embryo Stage 22 metanephros (week 8)
|}

[[File:Stage_22_image_189.jpg|400px]]

===Fetal===
[[File:Fetal_10wk_urogenital_1.jpg|thumb|early fetal kidney]]

<gallery>
File:Human_fetal_kidney_histology_01.jpg
File:Human_fetal_kidney_histology_02.jpg
File:Human_fetal_kidney_histology_03.jpg
File:Human_fetal_kidney_histology_04.jpg
</gallery>

== Nephron ==
[[File:Gray1128.jpg|thumb|Adult nephron structure]]
[[File:Nephron histology.jpg|thumb|Nephron histology]]

{| border='0px'
|-
{{Nephron movie}}
| valign="top" |'''Early Renal Development'''

'''Legend'''

* '''Uteric Bud''' - developing ureter, pelvis, calyces, collecting ducts
* '''Metanephric Blastema''' (intermediate mesoderm) - developing glomeruli, capsule, nephron tubules

Development has four developmental stages:
# '''vesicle''' (V) stage (13-19 weeks)
# '''S-shaped body''' (S) stage ( 20-24 weeks)
# '''capillary loop''' (C) stage (25-29 weeks)
# '''maturation''' (M) stage (infants aged 1-6 months)

'''Links:''' [[Quicktime Development Animation - Renal|Quicktime version]] | [[Development Animation - Urogenital Sinus|Animation - Urogenital Sinus]] | [[Renal System Development]]
|-
|}

===Nephron Development===
* disorganised mesenchymal cells become a highly organised epithelial tubule
* Condensation - groups of about 100 cells condense tightly together to form a distinct mass
* Epithelialisation - condensed cells lose their mesenchymal character and gain epithelial
* At end of this period formed a small epithelial cyst complete with a basement membrane, cell-cell junctions and a defined cellular apico-basal polarity.

===Early morphogenesis===
[[File:Renal - podocyte development 01.jpg|thumb|Renal - podocyte development]]
* cyst invaginates twice to form a comma
* then a S-shaped body one invagination site later becomes the glomerular cleft
* At about this time blood vessel progenitors invade cleft to begin construction of vascular component of glomerulus
* Tubule maturation specialised transporting segments of nephron differentiate complex of convoluted tubules is created

[[File:Glomerular podocyte cartoon.jpg|500px]]

===Adult nephron structure===
* mean glomerular number shown to level at 36 weeks
** about 15,000 at 15 weeks
** about 740,000 at 40 weeks.

* key structure of the adult nephron is the glomerulus (renal corpuscle), which represents the vascular/renal interface.

<gallery>
File:Nephron_histology_01.jpg|Glomerulus structure
File:Nephron_histology_02.jpg|Vascular and renal poles
</gallery>

'''Related Images:''' [[:File:Nephron_histology.jpg|Nephron histology overview]] | [[:File:Nephron_histology 01.jpg|glomerulus structure]] | [[:File:Nephron_histology 02.jpg|vascular and renal poles]]

==Renal Vascular==
===Renal Arteries===
{|
| {{Renal vascular movie}}
|
* starts in week 5 and is completed by week 15.
* week 6 - the kidneys begin to change their relative position, described as "ascent of the kidneys", to their correct anatomical position.
* week 9 - the rising movement is completed.
* During the ascent, the kidneys also become vascularised via the dorsal aorta.
* As this ascent occurs, the mesonephric ducts and the ureters enter the wall of the developing bladder.
|}
* Arise with ascent and inferior branches lost
* Sequential, 25% population have 2 or more renal arteries
* branch of abdominal aorta, divides into 4-5 branches
** each gives off small branches to suprarenal glands, ureter, surrounding cellular tissue and muscles
* Frequently a second renal artery (inferior renal) from abdominal aorta at a lower level, supplies lower portion of kidney.

===Renal Venous===
{|
| [[File:Embryo_renal_venous_cartoon.jpg|300px]]
| [[File:Adult_renal_venous_cartoon.jpg|300px]]
|-
| Embryo renal venous
| Adult renal venous
|}

==Endocrine Kidney==
Covered also in Endocrine Development lecture
* Renin - Increase Angiotensin-aldosterone system
* Prostaglandins - decrease Na+ reabsorption
* Erythropoietin - Increase Erythrocyte (rbc) production
* 1,25 (OH)2 vitamin D - Calcium homeostasis
* Prekallikreins - (plasma protein inactive precursor of kallikrein) Increase kinin production (altered vascular permeability)

==Cloaca==
[[File:Endoderm_cartoon.jpg|File:Endoderm development]]
* hindgut region ending at the cloacal membrane
* divided (ventro-dorsally) by the urogenital septum
** ventral - common urogenital sinus
** dorsal - rectum

{| border='0px'

|-
| {{Renal overview movie}}
| {{Urogenital_septum_movie}}
|}

===Common urogenital sinus===
* superior end continuous with '''allantois'''
* common urogenital sinus and mesonephric duct fuse (connect)
* differentiates to form the bladder
* inferior end forms '''urethra'''
** this will be different in male and female development

===Urinary Bladder===
[[File:Adult_bladder.jpg‎|thumb|Adult bladder]]
* early origins of the bladder at the superior end of the common urogenital sinus
*8 open inferiorly to the cloaca and superiorly to the allantois
* Septation of the claoca - divides the anterior region to the primordial bladder component from the posterior rectal component.
* associated ureters and urethra

Dorsal view of developing bladder

[[Media:Trigone_3.mov|Trigone formation animation]]

* Ultrasound measurement of the bladder size can be used as a diagnostic tool for developmental abnormalities.

===Bladder Structure===
[[File:Bladder histology.jpg|thumb|Bladder histology]]
Can be described anatomically by its 4 layers from outside inward:
* Serous - the superior or abdominal surfaces and the lateral" surfaces of the bladder are covered by visceral peritoneum, the serous membrane (serosa) of the abdominal cavity, consisting of mesthelium and elastic fibrous connective tissue.
* Muscular - the detrusor muscle is the muscle of the urinary bladder wall.
* Submucosa - connects the muscular layer with the mucous layer.
* Mucosa - (mucus layer) a transitional epithelium layer formed into folds (rugae).

===Detrusor Muscle===
* The adult detrusor muscle consists of three layers of smooth (involuntary) muscle fibres.
** external layer - fibres arranged longitudinally
** middle layer - fibres arranged circularly
** internal layer - fibres arranged longitudinally

===Ureter Development===
* The adult ureter is a thick-walled muscular tube, 25 - 30 cm in length, running from the kidney to the urinary bladder.
* Anatomically can be described in two parts the abdominal part (pars abdominalis) and pelvic part (pars pelvina).
* The ureter is composed of three layers: outer fibrous layer (tunica adventitia), muscular layer (tunica muscularis) and mucous layer (tunica mucosa).
* The muscular layer can also be subdivided into 3 fibre layers: an external longitudinal, a middle circular, and an internal longitudinal.

===Urethra Development===
* Further development of the urinary system varies depending on the sex of the embryo.
* Males - the pelvic urethra forms the membranous urethra, the prostatic urethra and penile urethra. (The sex of the above animation and sections is male)
* Females - the pelvic urethra forms the membranous urethra and the vestibule of the vagina.

==Abnormalities==
[[File:Australian_abnormalities_pie_urogen.png|thumb]]
===Horseshoe Kidney===

{|
| [[File:Horseshoe kidney.jpg|400px]]
|
* fusion of the lower poles of the kidney.
* During migration from the sacral region the two metanephric blastemas can come into contact, mainly at the lower pole.
* The ureters pass in front of the zone of fusion of the kidneys.
* The kidneys and ureters usually function adequately but there is an increased incidence of upper urinary tract obstruction or infection.
* Some horseshoe variations have been described as having associated ureter abnormalities including duplications.
|}
===Kidney Vascular===
Supernumerary renal arteries

[[File:Accessory_renal_artery.jpg|300px]] [[File:Multiple_renal_arteries_01.jpg|300px]]

Supernumerary renal vein

[[File:Supernumerary_renal_vein_02.jpg|300px]] [[File:Supernumerary_renal_vein_04.jpg|300px]]

===Urorectal Septum Malformation===
* thought to be a deficiency in caudal mesoderm which in turn leads to the malformation of the urorectal septum and other structures in the pelvic region.
* Recent research has also identified the potential presence of a persistent urachus prior to septation of the cloaca (common urogenital sinus).

===Bladder===
* absent or small bladder -
associated with renal agenesis.

===Bladder Exstrophy===
[[File:Bladder_Exstrophy.jpg|thumb|Bladder_Exstrophy]]
* developmental abnormality associated with bladder development.
* origins appear to occur not just by abnormal bladder development, but by a congenital malformation of the ventral wall of abdomen (between umbilicus and pubic symphysis).
* There may also be other anomolies associated with failure of closure of abdominal wall and bladder (epispadias, pubic bone anomolies).

===Ureter and Urethra===
* Ureter - Duplex Ureter
* Urethra- Urethral Obstruction and Hypospadias

===Polycystic Kidney Disease===
[[File:Multicystic kidney.jpg|thumb|Multicystic kidney]]
* diffuse cystic malformation of both kidneys
* cystic malformations of liver and lung often associated, Often familial disposition
* Two types
** Infantile (inconsistent with prolonged survival)
** Adult (less severe and allows survival)
* Autosomal dominant PKD disease - recently identified at mutations in 2 different human genes encoding membrane proteins (possibly channels)

===Wilms' Tumor===
[[File:Wilms_tumor.jpg|thumb|Wilms' tumor]]
* (nephroblastoma) Named after Max Wilms, a German doctor who wrote first medical articles 1899
* most common type of kidney cancer children
* WT1 gene - encodes a zinc finger protein
* Both constitutional and somatic mutations disrupting the DNA-binding domain of WT1 result in a potentially dominant-negative phenotype
* some blastema cells (mass of undifferentiated cells) persist to form a ‘nephrogenic rest’
* Most rests become dormant or regress but others proliferate to form hyperplastic rests
* any type of rest can then undergo a genetic or epigenetic change to become a neoplastic rest
* can proliferate further to produce a benign lesion (adenomatous rest) or a malignant Wilms’ tumour

=== Prune Belly Syndrome ===
<gallery>
File:Hydronephrosis.jpg|
File:Renal_outflow_obstruction.jpg|
File:Prune_belly.jpg|Prune_belly
</gallery>
* lower urinary tract obstruction
* mainly male
* fetal urinary system ruptures leading to collapse and "prune belly" appearance.

==Additional Images==
<gallery>
File:Stage 11 historic-Atwell1930-3b.jpg|Stage 11 historic Atwell (1930)
File:Stage_11_historic-Heuser1930-1c.jpg|Stage 11 historic Heuser (1930)
File:Gray1128.jpg|Nephron structure
File:Nephron physiology.jpg|Nephron physiology
File:Gray1127.jpg|Kidney and adrenal gland (adult)
File:Endoderm cartoon.jpg|Endoderm cartoon
File:Fetal 10wk urogenital 1.jpg|Fetal urogenital region most lateral right
File:Fetal 10wk urogenital 2.jpg|Fetal urogenital region lateral right
File:Fetal 10wk urogenital 3.jpg|Fetal urogenital region medial
File:Fetal 10wk urogenital 4.jpg|Fetal urogenital region midline
File:Bladder_histology.jpg|Bladder histology
File:Australian_abnormalities_pie_urogen.png
File:Horseshoe kidney.jpg|Horseshoe kidney
File:Hydronephrosis.jpg|Hydronephrosis
File:Renal_outflow_obstruction.jpg‎|Renal outflow obstruction
File:Bladder Exstrophy.jpg‎|Bladder Exstrophy
</gallery>

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter 13 p303-346
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 10 p261-306
* '''Before We Are Born''' (5th ed.) Moore and Persaud Chapter14 p289-326
* '''Essentials of Human Embryology''', Larson Chapter 10 p173-205
* '''Human Embryology''', Fitzgerald and Fitzgerald Chapter 21-22 p134-152

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 Chapter 14 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.section.3498 Intermediate Mesoderm] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3498&rendertype=figure&id=A3500 Figure 14.18. General scheme of development in the vertebrate kidney] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6814 Figure 23-23. Mechanism of mesenchymal inductive effect on the ureteric bud] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3498&rendertype=figure&id=A3507 Figure 14.21. Ureteric bud growth is dependent on GDNF and its receptor]

* '''Molecular Cell Biology''' by Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. New York: W. H. Freeman & Co.; c1999 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6811 Reciprocal Epithelial-Mesenchymal Interactions Regulate Kidney Development] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6811 Figure 23-21. Embryonic development of the kidney]

===Reviews===
* Quaggin SE, Kreidberg JA. Development of the renal glomerulus: good neighbors and good fences. Development. 2008 Feb;135(4):609-20. [http://www.ncbi.nlm.nih.gov/pubmed/18184729 PMID: 18184729]
* Brenner-Anantharam A, Cebrian C, Guillaume R, Hurtado R, Sun TT, Herzlinger D. Tailbud-derived mesenchyme promotes urinary tract segmentation via BMP4 signaling. Development. 2007 May;134(10):1967-75. [http://www.ncbi.nlm.nih.gov/pubmed/17442697 PMID: 17442697]
* [http://www.nature.com/ng/meetings/nephrogenetics/index.html Forefronts Symposium on Nephrogenetics: from development to physiology March 8-11, 2007 Danvers, MA] A meeting to synthesize an integrated view of the normal development and function of the kidney from the genetic standpoint.
* Costantini F. Renal branching morphogenesis: concepts, questions, and recent advances. Differentiation. 2006 Sep;74(7):402-21. [http://www.ncbi.nlm.nih.gov/pubmed/16916378 PMID: 16916378]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=intermediate_mesoderm intermediate mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=kidney_development kidney development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=renal_development renal development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=ureteric+bud ureteric bud] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=nephron_development nephron development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=bladder+development bladder development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=intermediate_mesoderm intermediate mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=kidney_development kidney development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=renal_development renal development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=ureteric_bud ureteric bud] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=nephron_development nephron development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=bladder+development bladder development]

== Terms ==
* '''bladder exstrophy''' - A congenital malformation with bladder open to ventral wall of abdomen (between umbilicus and pubic symphysis) and may have other anomolies associated with failure of closure of abdominal wall and bladder (epispadias, pubic bone anomolies).
* '''blastema''' - Term used to describe a mass of undifferentiated cells.
* '''diabetes insipidus''' - The disorder is related to the hormone antidiuretic hormone (ADH, also called vasopressin) its synthesis, secretion, receptors and signaling pathway. In diabetes insipidus there is an excretion of large amounts (up to 30 litres/day) of a watery urine and an unremitting thirst.
* '''hydronephrosis''' - (congenital hydronephrosis, Greek, ''hydro'' = water) A kidney abnormality due to partial or complete obstruction at the pelvi-ureteric junction. This leads to a grossly dilated renal pelvis causing extensive renal damage before birth.
* '''hyperplastic rests''' - In kidney development, embryonic blastema cells can persist and proliferate to form a pool of cells, which under either genetic or epigenetic influence can then change to become a neoplastic rest. Normally the majority of nephrogenic rests either regress or become dormant.
* '''mesonephros''' - The second temporary stage of kidney development (pro-, meso-, meta-). The intermediate mesonephros develops and disappears with the exception of its duct, the '''mesonephric duct''', which will form the male reproductive duct system. In males, the mesonephric tubules go on to form the ducts of the testis. In females, these degenerate. A few mesonephric tubules remain as efferent ductules in the male and vestigial remnants in the female.
* '''mesonephric duct''' - (= Wollfian duct) An early developing urogenital duct running the length of the embryo that will differentiate and form the male reproductive duct system. In females this duct degenerates (some remnants may remain associated in broad ligament).
* '''metanephros''' - The adult kidney, third stage of mammalian kidney (pro-, meso-, '''meta-''') development within the intermediate mesoderm.
* '''metanephric cap''' - In kidney development, the intermediate mesoderm which surrounds the ureteric bud and will develop into nephrons.
* '''multicystic kidney''' - There is no functional kidney tissue present in the kidney and it is replaced by a multilocular cyst. This is non-familial and is produced by atresia of a ureter and is always unilateral.
* '''neoplastic rest''' - In kidney development, a neoplastic rest can develop under either genetic or epigenetic influence from a hyperplastic rest, originating from an embryonic blastema cell. Normally the majority of nephrogenic rests either regress or become dormant.
* '''nephrogenic rest''' - A kidney term used to describe the embryonic blastema cells which persist and under either genetic or epigenetic can change to become a neoplastic rest. These neoplastic rests can develop postnatally as a benign form (adenomatous rest) or a malignant [W.htm#Wilms_tumour Wilm's tumour] form. The rests are further characterised by the time of generation leading to different anatomical kidney locations: early intralobar nephrogenic rests (within the renal lobe) and late pelilobar nephrogenic rests (periphery of the renal lobe).
* '''nephron''' - (Greek, ''nephros'' = kidney) The functional unit of the kidney.
* '''nephros''' - (Greek, ''nephros'' = kidney) Term used to describe features associated with the kidney. (pronephros, mesonephros, metanephros, nephric, nephron, nephroblastoma).
* '''podocyte''' - (visceral epithelial cell) kidney glomerulus cell forming the main component of the glomerular filtration barrier.
* '''podocyte specific proteins''' - podocalyxin, glomerular epithelial protein-1, podocin, nephrin, synaptopodin, and alpha-actinin-4), podocyte synthesized proteins (vascular endothelial growth factor and novH), transcription factors (WT1 and PAX2).
* '''pronephros''' - (Greek, ''pro'' = before) The first temporary stage of kidney development (pro-, meso-, meta-). This forms the kidney of primitive fish and lower vertebrates. Kidney development occurs within the intermediate mesoderm interacting with endoderm. In humans, this very rudimentary kidney forms very early at the level of the neck. It is rapidly replaced by the mesonephros, intermediate stage kidney, differentiating in mesoderm beneath.
* '''proteinuria''' - The abnormal presence of protein in the urine and an indicator of diesease including diabetic kidney disease (DKD, diabetic nephropathy).
* '''renal''' - (Latin, ''renes'' = kidney) Term used in relation to the kidney and associated structures (renal pelvis, renal artery)
* '''ureter''' - The two ureters are hollow tubes that link and carries urine from kidney to the bladder. The tubes have a muscular wall lined with transitional epithelium.
* '''urethra''' - The single muscular tube that links and carries urine from the bladder to the exterior. In humans, the urethral length differs between the sexes (male longer, female shorter).
* '''urinary''' - Term used to describe all components of the kidney system including the bladder, ureters and urethra.
* '''urine''' - Term used to describe the liquid waste produced by the kidney, stored in the bladder and excreted from teh body through the urethra.
* '''urorectal septum''' - (URS) The structure which develops to separate the cloaca (common urogenital sinus) into an anterior urinary part and a posterior rectal part.
* '''Wilms' tumour''' - A form of kidney/renal cancer (nephroblastoma) named after Dr Max Wilms who first described the tumor. This childhood kidney cancer is caused by the inactivation of a tumour suppressor gene (BRCA2) or Wilms tumor-1 gene (Wt1) and is one of the most common solid tumors of childhood, occurring in 1 in 10,000 children and accounting for 8% of childhood cancers. Wt1 also required at early stages of gonadal development. (More? [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=194070 OMIM - Wilm's tumour] | [http://www.whonamedit.com/doctor.cfm/2109.html Dr Max Wilms])
* '''Wilms' tumor 1-associating protein''' - (WTAP) protein expressed in extraembryonic tissues and required for the formation of embryonic mesoderm and endoderm.
* '''Wolffian duct''' - (= mesonephric duct, preferred terminology), runs from the mesonephros to cloaca, differentiates to form the male vas deferens and in the female regresses. Named after Caspar Friedrich Wolff (1733-1794), a German scientist and early embryology researcher and is said to have established the doctrine of germ layers. (More? [http://www.whonamedit.com/doctor.cfm/2433.html Caspar Friedrich Wolff])

----

{{2012ANAT2341}}

----

[[Category:Renal]]

Lecture - Genital Development

2013-09-21T05:25:26Z

Z3283213:

== Introduction ==

[[File:Human idiogram.gif]] [[File:Historic-testis.jpg|240px]] [[File:Historic-ovary.jpg|240px]]

This section of notes covers genital development. Differences in development are dependent on a protein product of the Y chromosome SRY gene. Mesonephric duct (Wolffian Duct) and paramesonephric (Mullerian Duct) contribute the majority of male and female internal genital tract respectively.

Lecture Date: 2013-09-24 Lecture Time: 16:00 Venue: Biomedical Theatre E Speaker: Steve Palmer

|}

== Objectives ==
* Understand the development of the gonads in males and females
* Understand the chromosomal basis of sex determination
* Understand the differences in male/female internal duct develpoment.
* Understand the origins of the external genitalia
* Understand the developmental abnormalities in male and female development.

==Textbooks==
===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Genital Links}} | [[2010_Lecture_16|2010 Lecture]]
|}
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00012-6 Chapter 12 - Urogenital System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10015-6 Chapter 15 - Development of the Urogenital System]
|}

:'''Links:''' [[Embryology Textbooks]] | [http://www.ncbi.nlm.nih.gov/pubmed/17237341 Review of mammalian sex determination]

==Movies==

{|
| {{Genital cartoons}}
| {{Gonad vascular movie}}
|}

== Objectives ==
* Understand the development of the gonads in males and females.
* Understand the chromosomal basis of sex determination.
* Understand the differences in male/female internal duct develpoment.
* Understand the origins of the external genitalia.
* Understand the developmental abnormalities in male and female development.

==Stages of Sexual Differentiation ==

# Development of the '''indifferent gonad''' - (genital ridge) early embryo
# Differentiation of gonad - ('''testis or ovary''') late embryo, defining event in sexual differentiation
# Differentiation of '''internal genital organs''' and ducts - late embryo to fetal
# Differentiation of '''external genitalia''' - fetal
# Development of '''secondary sexual characteristics''' - puberty

[[File:Stage22 mesonephros.jpg|thumb|Stage 22 mesonephros]]

[[File:Urogenital indifferent.jpg|240px|Urogenital Indifferent]] [[File:Urogenital male.jpg|240px|Urogenital Male]] [[File:Urogenital female.jpg|240px|Urogenital Female]]

==Human Timeline==
{|
|
* '''Week 3-4''' - primordial germ cells migrate during gastrulation
* '''Week 4''' - (24 days) intermediate mesoderm, pronephros primordium
* '''Week 5''' - (28 days) mesonephros and mesonephric duct
* '''Week 6''' - (35 days) ureteric bud, metanephros, genital ridge
* '''Week 7''' - (42 days) cloacal divison, gonadal primordium - indifferent to first appearance of testis cords
* '''Week 8''' - (49 days) paramesonephric duct, clear gonadal differentiation
* '''Week 9''' - (56 days) paramesonephric duct fusion (female)
* '''Week 15''' - (100 days) primary follicles (ovary)
| [[File:Amnion 001 icon.jpg|120px|link=Development Animation - Amniotic Cavity]]
|}

==1. Development of the indifferent gonad==
{|
|
* kidneys and genital ridge develop from '''intermediate mesoderm''', which lies between the lateral plate mesoderm and the somites.
* kidney develops in multiple stages, which occur in a rostrocaudal sequence; '''pronephros''' > '''mesonephros''' > '''metanephros''' (true adult kidney)
* earliest structure to form is the pronephros, in week 4, featuring a pronephric duct with associated nephrogenic mesenchyme.
* pronephros degenerates early on, leaving only the duct system running down to the cloaca – this becomes known as the '''mesonephric duct''' (Wolffian duct), in the embryo.
* next stage is the formation of the mesonephros, a series of mesonephric tubules in the mesenchyme that are induced by the mesonephric duct.
* mesonephros is a transient structure in mammals (In fish and amphibians it is the functioning adult kidney), but in mammals it serves mainly as the site for gonadal development.
| [[Image:Mesoderm cartoon4.gif]]
|}

[[File:Urogenital_sinus_001 icon.jpg|160px|link=Development_Animation_-_Urogenital_Sinus]] [[File:Adrenal_and_gonad_early_development.jpg|600px]]

Gonad and adrenal early development (not required to know molecular information)

==2. Differentiation of gonad into testis or ovary==
[[File:Human_Y_chromosome_SRY_region.jpg|thumb|Human Y chromosome - SRY region]]
===Chromosomal Sex Determination===

===Y chromosome ===
* [[Y Chromosome]] - 59 million base pairs, hypervariable in length, mostly non-functional repeats
* Current known protein-coding genes = 48 including ''SRY''
** ''SRY'' encodes a 204 amino acid protein (TDF) that is a member of the HMG (High mobility group) box class of DNA-binding proteins. Transcription factors bind to specific sites of DNA and regulates the transcription (expression) of other genes.

===X chromosome===

* [[X Chromosome]] - 155 million base pairs, contains about 5% of the haploid genome and encodes house-keeping and specialized functions.
* Genes such as Wnt-4 and DAX-1 necessary for initiation of female pathway ovary development
* An early discovery (1961) was that in order to have correct levels of X chromosome gene/protein expression (gene dosage), females must "inactivate" a single copy of the X chromosome in each and every cell. The initiator of the X inactivation process was discovered (1991) to be regulated by a region on the inactivating X chromosome encoding an '''X''' '''i'''nactive '''s'''pecific '''t'''ranscript (XIST), that acts as RNA and does not encode a protein.
* The genetic content of the X chromosome has been strongly conserved between species because these genes have become adapted to working as a single dose - Ohno's law
* X inactivation occurs randomly throughout the embryo, generating a mosaic of maternal and paternally derived X chromosome activity in all tissues and organs. This can be seen in the fur colour of tortoiseshell cats.

Overview - [http://www.ncbi.nlm.nih.gov/books/NBK26940/figure/A3716 MBoC - Figure 20-18. Influence of Sry on gonad development] | [http://www.ncbi.nlm.nih.gov/books/NBK26940/bin/ch20f18.jpg image] (image provides a good overview of the anatomy of sex determination, I will refer to this in the lecture and practical class)

===Supporting Cells===
* So called because they "support" the germ cells
'''Males'''
* develop as '''Sertoli cells'''
* SRY is expressed in the primordia of the supporting cells, transforming them into Sertoli cells that surround the germ cells and form testis cords
* SRY is not expressed in the other cell types of the gonad
** therefore the Sertoli cells instruct the germ cells and the steroid secreting cells to take the male path of development
* Embryonic Sertoli cells secrete anti-Mullerian hormone (AMH)
* Adult Sertoli cells line the inside of the seminiferous tubules and support spermatogenesis.
'''Females'''
* develop as Follicle cells ('''granulosa cells''')
* Follicle cells surround and nurture the developing oocytes
* In response to FSH, follicle cells proliferate
** After ovulation, these cells become luteal cells of the corpus luteum secreting progesterone and oestrogens

===Steroid secreting cell lineage===
'''Male'''
* Develop into '''Leydig cells''' (interstitial cells) which sit outside the seminiferous tubules
* Secrete testosterone in response to luteinizing hormone from the pituitary

'''Female'''
* Develop into '''theca cells''' that secrete androstenedione which can be converted by the follicle cells into estrogens

===Primordial Germ Cells===
[[File:Stage9_bf2-primordial_germ_cell_region.jpg|thumb|Primordial germ cell region (Stage 9)]]
[[File:Stage 13 image 086.jpg|thumb|Genital Ridge (Stage 13)]]
* Primordial germ cells (PGCs) are thought to be the first population of cells to migrate through the primitive streak in early gastrulation (week 3)
* cells then lie at the hindgut yolk sac junctional region
* later migrate into the genital ridge (germinal ridge) in early embryonic development.

{| border='0px'
|+ '''Mouse - Primordial Germ Cell Migration'''
|-
| [[File:Primordial germ cell 001 icon.jpg|120px|link=Quicktime_Movie_-_Primordial germ cell migration 01]]
| [[File:Primordial germ cell 002 icon.jpg|120px|link=Quicktime_Movie_-_Primordial germ cell migration 02]]
| [[File:Primordial germ cell 003 icon.jpg|120px|link=Quicktime_Movie_-_Primordial germ cell migration 03]]
|-bgcolor="a3bfb1"
| E9.0 Migration
| E9.5 Migration
| E10.5 Migration
|-bgcolor="F5FFFA"
| [[Quicktime_Movie_-_Primordial germ cell migration 01|Quicktime]] | [[Movie_-_Primordial germ cell migration 01|Flash]]
| [[Quicktime_Movie_-_Primordial germ cell migration 02|Quicktime]] | [[Movie_-_Primordial germ cell migration 02|Flash]]
| [[Quicktime_Movie_-_Primordial germ cell migration 03|Quicktime]] | [[Movie_-_Primordial germ cell migration 03|Flash]]
|-
|}

* '''Not the primordial germ cells which respond to SRY''' presence or absence, but the supporting cells within the developing gonad.
** Germ cells occasionally migrate by mistake into the developing adrenal gland and in the absence of sertoli cells telling them what to do, abnormally begin to develop as oocytes, even in males

:'''Links:''' [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A4665&rendertype=figure&id=A4669 Germ cell migration pathway]

===Gametogenesis===
* forming PGCs as a small population of migratory cells
* enter the gonad where they undergo several rounds of mitotic cell division
* female - the germ cells enter meiosis and become arrested at the dictyate (diplotene) stage of meiotic prophase 1. All oocytes are at this stage at birth
* male - the germ cells are enclosed by the developing Sertoli cells and are induced to arrest differentiation and cell division as T1 prospermatogonia until after birth.

:'''Links:''' [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3729&rendertype=figure&id=A3735 Image - Spermatogenesis] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A4695&rendertype=figure&id=A4715 Image -Oogenesis]

==3. Differentiation of internal genital organs and ducts==
[[File:Stage_22_Urogenital_1l.jpg]]

Human embryo (Carnegie stage 22, week 8) pelvic level cross-section.
===Male===
{|
| valign="top" | This looped animation shows the development of the male gonad showing medullary sex cords.

* The paramesonephric duct (red, left) degenerates under the influence of anti-Mullerian hormone (AMH) secreted by sertoli cells.
* The mesonephric duct (purple) is maintained and differentiates under the influence of Testosterone secreted by Leydig cells. Within the testes these mesonephric tubules grow towards the testis cords and will form the rete testis. The mesonephric duct extending out of the gonad forms the ductus deferens.
* The testis cords (orange) containing the Sertoli cells and the germ cells (which are arrested as T1 prospermatogonia until after birth) later differentiate into seminiferous tubules which become hollow and actively produce spermatazoa during puberty.

The tunica albuginea (white) covers the testis and bands extend inward to form connective tissue septa.
|
{{Testis movie}}
|}

===Anti-Mullerian Hormone===
Anti-Mullerian hormone (AMH) or Mullerian Inhibiting Substance (MIS) hormone with at least two gonadal related functions:
* In males, it is produced by embryonic Sertoli cells and causes the loss of the paramesonephric (Mullerian) duct system that forms the internal female genital tract.
* In females, it is produced after puberty by follicle cells and suppresses the development of other primary follicles, thus restricting the number of follicles stimulated by FSH.

===Female===
{|
| valign="top" | This looped animation shows the development of the female gonad showing cortical sex cords.

* The mesonephric duct (purple) degenerates, small remnants may remain as epoophoron and paroophoron (in the mesentry of the ovary) and Gartner's cycts (near vagina).
* The paramesonephric duct (red, left) grows forming the oviducts (fallopian tubes) and the end opens into the peritoneal cavity and terminates in fimbria (finger-like extensions). Away from the ovary, the two paramesonephric ducts fuse in the midline to form the uterus.
* After entry of the germ cell into meiosis they are called oocytes and they are surrounded by the derivatives of the supporting cell lineage - the follicle cells or granulosa cells.
* About 95% of the germ cells that entered meiosis in the female will be lost by a process called follicular atresia (see graph. Only about 400,000 remain at the time of puberty.

[[File:Infant ovary.jpg|300px]] [[File:Human_ovary_non-growing_follicle_model.jpg|300px]]
| {{Ovary movie}}
|}

===Uterus Development===

* '''Week 7''' – duct preservation or regression begins

{{Uterus movie}}

Paramesonephric duct development

===Vagina Development===

* The embryonic origin of the vagina has been a historically hotly debated issue with several different contributions and origins described.
* Current molecular studies show the whole vagina is derived from the intermediate mesoderm-derived Müllerian duct (see review <ref><pubmed>19598112</pubmed></ref>)
** bone morphogenic protein 4 (BMP4) reshapes the duct into the vaginal primordium.
* exhibits different features from the uterus
** stratified squamous epithelium
** insensitivity to anti-Müllerian hormone

:'''Links:''' [[Vagina Development]]

==4. Differentiation of External Genitalia==
[[File:Gray1119.jpg|thumb|Historic diagram of external development]]
[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A972&rendertype=box&id=A1026 Endocrinology - Diagram of the development of the external genitalia] | [http://www.ncbi.nlm.nih.gov/books/NBK29/bin/ch6fb5.jpg image]

* external genitalia are initially identical and undergo male and female differentiation under the influence or absence of steroidal sex hormones.
* Indifferent stage ‐ cloaca divided by proliferating mesenchyme forming the urorectal septum which separates the ventral urogenital sinus from the dorsal rectum.
* Difference stage ‐ locally in this region the presence or absence of '''dihydrotestosterone''' (DHT), generated from testosterone, determines male/female development.

===Dihydrotestosterone (DHT)===
[[File:Testosterone_metabolism.jpg|thumb|Testosterone metabolism]]
* Male presence of DHT
** locally in this region leads to '''genital tubercle''' growth, form
** '''genital folds''' (urethral) initial maintenance and then fusion, forming perineal and penile raphe.
** '''labioscrotal swellings''' (lateral to urethreal folds) become the scrotum.
* Female absence of DHT
** genital tubercle remains small, bends caudally to form the clitoris.
** genital folds (urethral) persist, do not fuse, and form labia minora.
** open urogenital sinus forms a cleft into which urethra and vagina open.
** labioscrotal swellings become the labia majora.

===Female===
[[File:Newborn_uterus.jpg|thumb|Newborn uterus]]
This looped animation shows the development of external female genitalia from the indifferent external structure, covering the approximate period of week 9 to 12.

{{Female external movie}}

[[File:Urogenital_septum_001 icon.jpg|90px|link=Development_Animation_-_Urorectal_Septum]]

[[Development_Animation_-_Urogenital_Septum|Animation - Urorectal septum and division of the cloacal membrane]]

Note the original cloacal membrane becomes separated into the urogenital membrane and anal membrane. The urogenital folds beneath the genital tubercle remain separate (unfused), forming the inner labia minora and second outer skin folds form the larger labia majora either side of the developing vestibule of the vagina. Note at the top of the animation, the changing relative size of the genital tubercle as it forms the glans of the clitoris.

===Male Genitalia Development===
[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A972&rendertype=box&id=A1027 Endocrinology - Box 6.6 The roles of testosterone (T) and 5α-dihydrotestosterone (DHT)]

This looped animation shows the development of external male genitalia from the indifferent external structure, covering the approximate period of week 9 to 12.

{{Male external movie}}

==Gonad Descent==
{|
|
* Both kidney and gonads develop retroperitoneally, with the gonads moving into the abdomen or eventually into the scrotal sacs.
* During fetal development the gubernaculum and fetal growth in both male and female, changes the gonads’ relative positions finally reaching their adult locations.

Both female and male gonads undergo anatomical descent.

* '''Ovaries''' ‐ undergo caudal and lateral shifts to be suspended in the broad ligament of the uterus, gubernaculum does not shorten, it attaches to paramesonephric ducts, causing medial movement into the pelvis.

* '''Testes''' ‐ two anatomical phases in descent, transabdominal and transinguinal, under the influence of the shortening gubernaculum.
| {{Testis descent movie}}
|}

{|
| [[File:Testis_001 icon.jpg|200px|link=Development_Animation_-_Testis_Descent]]
| [[File:Testis-descent start.jpg|300px]] [[File:Testis-descent end.jpg|300px]]

:'''Links:''' [[Media:Testis Descent_001.mov‎|Quicktime movie]] | [[Quicktime Development Animation - Testis Descent|Quicktime]] | [[Development Animation - Testis Descent|Flash]] | [[Testis Development]] | [[Third Trimester]]
|}

The testis (white) lies in the subserous fascia (spotted) a cavity processus vaginalis evaginates into the scrotum, and the gubernaculum (green) attached to the testis shortens drawing it into the scrotal sac. As it descends it passes through the inguinal canal which extends from the deep ring (transversalis fascia) to the superficial ring (external oblique muscle). Descent of the testes into the scrotal sac begins generally during week 26 and may take several days. The animation shows the path of a single testis.

Data from a recent study of male human fetal (between 10 and 35 weeks) gonad position.

* 10 to 23 weeks - (9.45%) had migrated from the abdomen and were situated in the inguinal canal
* 24 to 26 weeks - (57.9%) had migrated from the abdomen
* 27 to 29 weeks - (16.7%) had not descended to the scrotum

Incomplete or failed descent can occur unilaterally or bilaterally, is more common in premature births, and can be completed postnatally.

==5. Postnatal - Puberty==
[[File:Puberty_growth.jpg|thumb|Puberty growth]]
Puberty can occur over a broad range of time and differently for each sex:
* girls (age 7 to 13)
* boys (age 9 to 15)

The physical characteristics that can be generally measured are: genital stage, pubic hair, axillary hair, menarche, breast, voice change and facial hair.

===Male===
* Testosterone - adult testes produce about 6-10 mg /day in males (~0.5 mg / day in females) carried in circulation by a specific carrier globulin.
* masculinizing androgen - also at puberty, spermatogenesis in males
* development of secondary sexual characteristics - body and facial hair growth (male pattern baldness)
* anabolic effect - metabolism towards conservation of amino acids, promoting protein synthesis, muscle development
* neural - libido in both sexes, male pattern behaviour
* Sustentacular (Sertoli) cells - produce anti-mullerian hormone (AMH) to puberty.
** '''AMH''' - anti-Müllerian hormone (Müllerian inhibiting factor (MIF), Müllerian-inhibiting hormone (MIH), and Müllerian-inhibiting substance (MIS)).
[[File:Male_testosterone_and_AMH_level_graph.jpg|500px]]

===Female===
[[File:XXhpgaxis.jpg|thumb|Female HPG Axis]]
In females, menarche (the first menstruation or a period) usually occurs after the other secondary sex characteristics, and will continue until menopause (permanent cessation of reproductive fertility).

The diagram shows the hormonal regulation pathway from the brain to the ovary and subsequent impact on uterine changes during the menstral cycle.

* '''GnRH''' = Gonadotropin-releasing hormone (GnRH). This peptide hormone is a decapeptide (10 amino acids) with a short half life (<15 minutes).
* '''LH''' = Luteinizing Hormone
* '''FSH''' = Follicle Stimulating Hormone

A similar endocrine axis is also found for regulation of the male gonad.

<gallery>
File:HPG female axis.jpg|Hypothalamus - Pituitary - Gonad (female)
File:HPG male axis.jpg|Hypothalamus - Pituitary - Gonad (male)
</gallery>

===Puberty Abnormalities===
* '''Precocious Puberty''' - Premature development of the signs of puberty which can occur in both girls (before age 7 or 8) and in boys (before age 9).
* '''Delayed Puberty''' - Determined in boys by a lack of increase in testicular volume by the age of 14 years. In girls, no breast development by the age of 13.5 years and a lack of menstruation by the age of 16 years. There can also be a "pubertal arrest" where there is no progress in puberty over 2 year period.

==Sex Differences in Adult and Developing Brains==

* not known significance of brain sex differences
* transient sex differences in gene expression in developing brains may cause permanent differences in brain structure
* may prevent as well, by compensating for potentially differentiating effects of sex differences in gonadal hormone levels and sex chromosomal gene expression

* Brains of males and females differ
** in regions specialized for reproduction
** in other regions (controlling cognition, etc) where sex differences are not necessarily expected
** Differentially susceptible to neurological and psychiatric disease

2 sources of sexually dimorphic information
* complement of sex chromosome genes
* mix of gonadal hormones

==Abnormalities==

===Sex Reversal===
* Where chromosomal sex does not match phenotypic sex i.e. XX males or XY females

XX males - usually caused by a transfer of some Y chromosome DNA onto the X chromosome
* Gonads develop as testes, everything looks normal internally and externally but infertile due to a failure of spermatogenesis
* Similar to Kleinfelters syndrome (XXY)

XY females - usually steroidal origin
* Main cause is Androgen Insensitivity Syndrome (AIS) Complete (CAIS) Partial (PAIS) and Mild (MAIS) usually caused by mutations of the gene encoding the androgen receptor ''AR'' gene located on the X chromosome
* 5-alpha-reductase deficiency - again leads to a lack of complete steroidal induction of external genitalia
* Rare mutations in key sex determining genes including deletion or mutations of ''SRY''

Human genital abnormalities are currently described as "Disorders of Sex Development" (DSD) and include: chromosomal, gonadal dysfunction, tract abnormalities, external genitalia and gonadal descent.

:'''Links:''' [[Genital System - Abnormalities]]

===Congenital adrenal hyperplasia===
* impairment of cortisol production by the adrenal cortex, is one of the most common causes of intersex genitalia at birth
* genetically male (XY) infants born with undervirilized genitalia are often assigned and reared as girls.

===Cryptorchidism===
[[File:Cryptorchidism.jpg|thumb|Cryptorchidism]]
* abnormality of either unilateral or bilateral testicular descent, occurring in up to 30% premature and 3-4% term males.
* Descent may complete postnatally in the first year, failure to descend can result in sterility.

Testis descent is thought to have 2 phases:
# transabdominal descent - dependent on insulin-like hormone 3 (INSL3).
# inguinoscrotal descent - dependent on androgens.

===Undescended Ovaries===
* reasonably rare gonad abnormality, often detected following clinical assessment of fertility problems and may also be associated with other uterine malformations (unicornuate uterus).
* Due to the relative positions of the male (external) and female (internal) gonads and the pathways for their movement, failure of gonad descent is more apparent and common in male cryptorchidism than female undescended ovaries.

===Hydrocele===
* Male Hydrocele is a fluid-filled cavity of either testis or spermatic cord, where peritoneal fluid passes into a patent processus vaginalis.
* Female Hydrocele is a similar, but rarer, fluid-filled cavity occuring in the female as a pouch of peritoneum extending into the labium majorum (canal of Nuck).

===Tract Abnormalities===

Many different forms
* Uterine: associated with other anomolies, unicornuate uterus
* Vagina: agenesis, atresia
* Ductus Deferens: Unilateral or bilateral absence, failure of mesonephric duct to differentiate

{|
| [[File:Uterine abnormalities.jpg|400px]]
| [[File:Unicornate uterus.jpg|400px|Unicornate uterus]]
|-
| Uterine abnormalities
| Unicornate uterus
|}

Uterine Duplication (uterus didelphys, double uterus, uterus didelphis) A rare uterine developmental abnormality where the paramesonephric ducts (Mullerian ducts) completely fail to fuse generating two separate uterus parts each connected to the cervix and having an ovary each.

Septate Uterus

Cervical: cervical agenesis, cervical duplication

Vaginal: Mayer-Rokitansky syndrome (MRK anomaly, Rokitansky-Küster-Hauser syndrome, RKH syndrome, RKH) congenital absence of the vagina, dyspareunia, vaginal agenesis.

==External Genitalia - Hypospadia==

* most common penis abnormality (1 in 300) from a failure of male urogenital folds to fuse in various regions and resulting in a proximally displaced urethral meatus.
* The cause is unknown, but suggested to involve many factors either indivdually or in combination including: familial inheritance, low birth weight, assisted reproductive technology, advanced maternal age, paternal subfertility and endocrine-disrupting chemicals. Infants with hypospadias should not undergo circumcision.

==Movies==

{| border='0px'
|-
| [[File:Urogenital_sinus_001 icon.jpg|90px|link=Quicktime Development_Animation_-_Urogenital_Sinus]]
| [[File:Urogenital_septum_001 icon.jpg|90px|link=Quicktime Development_Animation_-_Urogenital_Septum]]
| [[File:Gonad-icon.jpg|90px|link=Quicktime Development Animation - Ovary‎‎]]
| [[File:Gonad-icon.jpg|90px|link=Quicktime Development Animation - Testis‎‎]]
| [[File:Female_external_001 icon.jpg|90px|link=Quicktime Development_Animation_-_Genital_Female_External]]
| [[File:Male_external_001 icon.jpg|90px|link=Quicktime Development_Animation_-_Genital_Male_External]]
| [[File:Uterus_001 icon.jpg|90px|link=Quicktime Development_Animation_-_Uterus]]
| [[File:Testis_001 icon.jpg|90px|link=Quicktime Development_Animation_-_Testis_Descent]]
|-bgcolor="a3bfb1"
|  '''Urogenital Sinus'''
|  '''Urogenital Septum'''
|  ‎‎'''Ovary'''
|  '''Testis'''‎‎
|  '''Female External'''
|  '''Male External'''
|  '''Uterus'''
|  '''Testis Descent'''
|-bgcolor="F5FFFA"
| [[Quicktime Development_Animation_-_Urogenital_Sinus|Quicktime]] | [[Development_Animation_-_Urogenital_Sinus|Flash]]
| [[Quicktime Development_Animation_-_Urogenital_Septum|Quicktime]] | [[Development_Animation_-_Urogenital_Septum|Flash]]
| [[Quicktime Development Animation - Ovary|Quicktime]] | [[Development Animation - Ovary|Flash]]
| [[Quicktime Development Animation - Testis|Quicktime]] | [[Development Animation - Testis|Flash]]
| [[Quicktime Development_Animation_-_Genital_Female_External|Quicktime]] | [[Development_Animation_-_Genital_Female_External|Flash]]
| [[Quicktime Development_Animation_-_Genital_Male_External|Quicktime]] | [[Development_Animation_-_Genital_Male_External|Flash]]
| [[Quicktime Development_Animation_-_Uterus|Quicktime]] | [[Development_Animation_-_Uterus|Flash]]
| [[Quicktime Development_Animation_-_Testis_Descent|Quicktime]] | [[Development_Animation_-_Testis_Descent|Flash]]
|}

== References ==
<references/>
===Textbooks===
* '''Before We Are Born''' (5th ed.) Moore and Persaud Chapter 14 p289-326
* '''Essentials of Human Embryology''', Larson Chapter 10 p173-205
* '''Human Embryology''', Fitzgerald and Fitzgerald Chapter 21-22 p134-152

===Online Textbooks===
* '''Developmental Biology''' (6th ed.) Gilbert Chapter 14 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.section.3498 Intermediate Mesoderm]
* Historic - '''Text-Book of Embryology'''. Bailey, F.R. and Miller, A.M. (1921). New York: William Wood and Co. [[Book_-_Text-Book_of_Embryology_15#The_Genital_Glands|Chapter 15. The Genital Glands]]

===Reviews===
<pubmed>17237341</pubmed>| [http://physrev.physiology.org/content/87/1/1.long Physiol. Rev.] | [[Talk:BGD_Lecture_-_Sexual_Differentiation#Figure_Pages|Figure Links]]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=genital+development genital development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=gonad+development gonad development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=sex+determination sex determination]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=genital+development genital development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=gonad+development gonad development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=sex+determination sex determination]

==External Links==
{{External Links}}

* '''Embryo Images Unit:''' [http://www.med.unc.edu/embryo_images/unit-genital/genital_htms/genitaltoc.htm Urongenital Development] | [http://www.med.unc.edu/embryo_images/unit-genital/genital_htms/genital008.htm Internal Genitalia] | [http://www.med.unc.edu/embryo_images/unit-genital/genital_htms/genital017.htm Definitive Kidney] | [http://www.med.unc.edu/embryo_images/unit-genital/genital_htms/genital020.htm External Genitalia]

* '''Histology:''' [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/MaleRepro/malerepro.htm Male Reproductive System] | [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/FemaleRepro/femalerepro.htm Female Reproductive System]

ANAT2341 Lab 9 2013

2013-09-18T03:11:27Z

Z3283213: /* There will be no short answer/multiple choice test this week and next week due to time constraints */

=Oral presentation of group projects part 1=
==There will be no short answer/multiple choice test this week and next week due to time constraints==
However, please arrive on-time as we need the whole 2 hours to complete the oral presentations

'''Order of Presentations'''
#Treacher-Collins syndrome
#Campomelic dysplasia
#Cleidocranial dysplasia
#Gorlin syndrome/Basal cell nevus syndrome

===Dividing the tasks===
'''The oral and written reports should be divided into 3 equal sections.'''
#Developmental abnormalities of the disease, diagnosis and human genetics
#Genetics of the relevant mouse mutants and the resulting developmental abnormalities
#Using the mouse mutants to understand the developmental, cellular and molecular basis of the disease

Each member of the group should assume responsibility for one of these sections. The marks will be divided into 2 parts. A mark for the overall project and a mark for the section for which you have taken responsibility. Therefore, it is important to edit each others work and ensure that the overall product is integrated and well finished. Each person should identify which section they have taken chief responsibility for.

Groups that only have 2 members should divide their work by one student taking responsibility for part 1 and the other part 2, then part 3 should be shared equally. During the oral presentation, only one student should present part 3.

===Topics===
The selected topics will be updated when they have been chosen

{| class="pretty table"
|-bgcolor="lightsteelblue"
| <center>''' System '''</center>
| <center>''' Human disease '''</center>
| <center>''' OMIM '''</center>
| <center>''' Gene '''</center>
| <center>''' Relevant mouse models '''</center>

|-
| Skin
| Gorlin Sydndrome/Basal Cell Nevus Syndrome
| 109400
| ''PTCH1''
| K14-Cre Ptc mutants

|-
| Craniofacial
| Treacher-Collins Syndrome 1
| 154500
| ''TCOF1''
| Tcof1 mutants

|-
| Limb development
| Split-hand/foot malformation 1 with sensorineural hearing loss
| 220600
| ''DLX5''
| Dlx5/6 mutants

|-
| Gonadal development
| Campomelic Dysplasia
| 114290
| ''SOX9''
| Sox9 transgenics/LOF mutants

|-
| Heart development
| Holt-Oram Syndrome
| 142900
| ''TBX5''
| Tbx5 mutants

|-
| Kidney development
| Polycystic kidney disease, adult type I
| 173900
| ''PKD1''
| Pkd1,2 mutants

|-
|Multisystemic
|DiGeorge Syndrome
|188400
| ''TBX1''
| Multiple

|-
|Eye
|Aniridia
|106210
|''PAX6''
|Small eye (Sey)

|-
|Blood
|Omenn Syndrome
|603554
|''RAG1'' and ''RAG2''
|''Rag1'' mutant and ''Rag2'' knockin

|-
|Bone
|Cleidocranial Dysplasia
|119600
|''RUNX2''
|''Runx2'' mutant and knockout

|-
|Neural tube
|Neural tube defects including spina bifida
|182940
|''T''
|Tailless Brachyury mutants

|-
|Sexual differentiation
|Androgen Insensitivity Syndrome
|300068
|''AR''
|Tfm mice

|-
|Neural Crest Derivatives
|Waardenburg Syndrome Type 4
|277580
|''EDNRB''
|Endothelin-B receptor mutant

|}

ANAT2341 Lab 8 2013

2013-09-18T03:06:40Z

Z3283213: /* Oral presentation of group projects part 1 */

=Oral presentation of group projects part 1=
==There will be no short answer/multiple choice test this week and next week due to time constraints==
However, please arrive on-time as we need the whole 2 hours to complete the oral presentations

'''Order of Presentations'''
#Neural tube defects including spina bifida -
#Aniridia
#Polycystic kidney disease
#Split-hand/foot malformation with hearing loss

===Dividing the tasks===
'''The oral and written reports should be divided into 3 equal sections.'''
#Developmental abnormalities of the disease, diagnosis and human genetics
#Genetics of the relevant mouse mutants and the resulting developmental abnormalities
#Using the mouse mutants to understand the developmental, cellular and molecular basis of the disease

Each member of the group should assume responsibility for one of these sections. The marks will be divided into 2 parts. A mark for the overall project and a mark for the section for which you have taken responsibility. Therefore, it is important to edit each others work and ensure that the overall product is integrated and well finished. Each person should identify which section they have taken chief responsibility for.

Groups that only have 2 members should divide their work by one student taking responsibility for part 1 and the other part 2, then part 3 should be shared equally. During the oral presentation, only one student should present part 3.

===Topics===
The selected topics will be updated when they have been chosen

{| class="pretty table"
|-bgcolor="lightsteelblue"
| <center>''' System '''</center>
| <center>''' Human disease '''</center>
| <center>''' OMIM '''</center>
| <center>''' Gene '''</center>
| <center>''' Relevant mouse models '''</center>

|-
| Skin
| Gorlin Sydndrome/Basal Cell Nevus Syndrome
| 109400
| ''PTCH1''
| K14-Cre Ptc mutants

|-
| Craniofacial
| Treacher-Collins Syndrome 1
| 154500
| ''TCOF1''
| Tcof1 mutants

|-
| Limb development
| Split-hand/foot malformation 1 with sensorineural hearing loss
| 220600
| ''DLX5''
| Dlx5/6 mutants

|-
| Gonadal development
| Campomelic Dysplasia
| 114290
| ''SOX9''
| Sox9 transgenics/LOF mutants

|-
| Heart development
| Holt-Oram Syndrome
| 142900
| ''TBX5''
| Tbx5 mutants

|-
| Kidney development
| Polycystic kidney disease, adult type I
| 173900
| ''PKD1''
| Pkd1,2 mutants

|-
|Multisystemic
|DiGeorge Syndrome
|188400
| ''TBX1''
| Multiple

|-
|Eye
|Aniridia
|106210
|''PAX6''
|Small eye (Sey)

|-
|Blood
|Omenn Syndrome
|603554
|''RAG1'' and ''RAG2''
|''Rag1'' mutant and ''Rag2'' knockin

|-
|Bone
|Cleidocranial Dysplasia
|119600
|''RUNX2''
|''Runx2'' mutant and knockout

|-
|Neural tube
|Neural tube defects including spina bifida
|182940
|''T''
|Tailless Brachyury mutants

|-
|Sexual differentiation
|Androgen Insensitivity Syndrome
|300068
|''AR''
|Tfm mice

|-
|Neural Crest Derivatives
|Waardenburg Syndrome Type 4
|277580
|''EDNRB''
|Endothelin-B receptor mutant

|}

Lecture - Limb Development

2013-09-16T07:25:52Z

Z3283213:

==Introduction==
[[File:Appendicular skeleton.jpg|thumb|400px]]
This lecture is an introduction to the events in limb development. Cells of the ectoderm, cells derived from the dermatome and the hypaxial portion of the myotome mix with somatic component of the lateral plate mesoderm to give rise to the fore and hind limbs.

The appendicular skeleton consists of: Shoulder girdle, Upper limb (arm, hand), Pelvic girdle, Lower limb (leg, foot).

[[:File:Human_Carnegie_stage_1-23.jpg|Carnegie stage 1-23]]

==Lecture Objectives==
[[File:Stage14 sem2b-limb.jpg|thumb|Human Embryo stage 14 SEM]]

*Review of the subdivisions of mesoderm development.
*Differentiation of somites
*Development of the axial skeleton – skull and vertebral column.
*Resegmentation of the sclerotome
*Development of the vertebrae and their specializations.
*Development of the skull.
*Cartilage formation
*Bone formation
*Development of skeletal muscle

==Information==

Lecture Date: 2013-09-17 Lecture Time: 16:00 Venue: BioMed E Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Limb_development.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (chapter links only work with a UNSW connection).
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00016-3&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00016-3 Chapter 16 – Development of Limbs]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (chapter links only work with a UNSW connection).

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10018-1 Chapter 18 - Development of the Limbs]
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

* [[Musculoskeletal System - Limb Development|Limb Development]]
* [[Musculoskeletal System - Limb Abnormalities|Limb Abnormalities]]
* '''Developmental Dynamics''' - Special Issue: [http://onlinelibrary.wiley.com/doi/10.1002/dvdy.v240.5/issuetoc Special Issue on Limb Development] May 2011 Volume 240, Issue 5
|}

:'''Links:''' [[Embryology_Textbooks_-_UNSW|UNSW Textbooks]] | [[Embryology Textbooks]]

==Limb Buds==
* Limbs are initially undifferentiated mesenchyme (mesoderm) with an epithelial (ectoderm) covering. Uniform paddle shaped structures that grow outwards gradually.
* One the first noticeable changes is the development of a large blood vessel (marginal vein) which runs just underneath a thickening of the ectoderm at the tip of the limb bud called the Apical Ectodermal Ridge (AER).
* Positioning of the limbs is distant from final location

==Upper and Lower Limb==
[[File:Stage20-23 limbs.jpg|600px]]
[[File:Stage14_somites_limbbuds.png|thumb]]
Limb development occurs at different times for forelimbs and hindlimbs. In the mid-4th week, human upper limb buds first form and lower limbs about 2 days later. The limbs form at vertebra segmental levels C5-C8 (upper limbs) L3-L5 (lower limbs).

==Limb Axis Formation==

Four Concepts - much of the work has been carried out using the chicken and more recently the mouse model of development.

# Limb Initiation
# Proximodistal Axis
# Dorsoventral Axis
# Anteroposterior Axis

===Limb Initiation===
* Fibroblast growth factor (FGF) coated beads can induce additional limb
* FGF10 is expressed in lateral plate mesoderm prior to bud formation induces expression of FGF8 in the overlying ectoderm. FGF8 induces continued growth in the underlying mesoderm - thus a positive feedback loop
* Anterior boundary of Hoxc6 expression coincides with the position of forelimb development

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3941&rendertype=figure&id=A3953 Autoregulatory loop of induction between FGF10 and FGF8]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A1038&rendertype=figure&id=A1041 Site of FGF10 expression in the chick embryo]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3881 Positioning of the limb on the rostrocaudal (anteroposterior) axis is determined by the expression of Hox genes]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3882 Examples of Hox gene expression boundaries in the mouse Hoxb2 and Hoxb4]

===Limb Identity===

Forelimb and hindlimb (mouse) identity appears to be regulated by T-box (Tbx) genes, which are a family of transcription factors.
* hindlimb Tbx4 is expressed.
* forelimb Tbx5 is expressed.
* Tbx2 and Tbx3 are expressed in both limbs.

'''Related Research''' - [http://www.ncbi.nlm.nih.gov/pubmed/12490567?dopt=Abstract PMID: 12490567] | [http://dev.biologists.org/cgi/content/figsonly/130/3/623 Development 2003 Figures] | [http://dev.biologists.org/cgi/content/full/130/3/623/FIG1 Scanning electron micrographs of E9 Limb bud wild-type and Tbx5del/del] [http://dev.biologists.org/cgi/content/full/130/3/623/FIG7 A model for early stages of limb bud growth] | [http://www.ncbi.nlm.nih.gov/pubmed/12736217?dopt=Abstract PMID: 12736217] | [http://dev.biologists.org/cgi/content/figsonly/130/12/2741 Development 2003 Figures]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3928&rendertype=figure&id=A3936 Tbx4 expression can turn an experimentally induced forelimb into a hindlimb]

==Axes and Morphogens==
[[File:Limb bud geometry and patterning.jpg|thumb|Limb bud geometry and patterning]]
* '''Anteroposterior''' - (Rostrocaudal, Craniocaudal, Cephalocaudal) from the head end to opposite end of body or tail.
* '''Dorsoventral''' - from the spinal column (back) to belly (front).
* '''Proximodistal''' - from the tip of an appendage (distal) to where it joins the body (proximal).

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3885&rendertype=figure&id=A3902 Model of patterning signals in the vertebrate limb]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3792&rendertype=figure&id=A3812 Diffusible morphogens create a concentration gradient accross an embryonic field]

===Proximodistal Axis===
* Apical Ectodermal Ridge (AER) initially formed at the site of FGF10 induction
* then AER secretes FGF8 and FGF4 slightly later
* FGFs stimulate proliferation and outgrowth in the underlying mesenchyme

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb017.htm limb development at embryo images online]

=====Morphogen production from the AER - The Fibroblast Growth Factors (FGFs)=====
* 22 FGF genes identified in humans
* bind membrane tyrosine kinase receptors
* Patterning switch with many different roles in different tissues

FGF receptors
* comprise a family of at least 4 related but individually distinct tyrosine kinase receptors (FGFR1- 4) similar protein structure
* 3 immunoglobulin-like domains in extracellular region
* single membrane spanning segment
* cytoplasmic tyrosine kinase domain

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A1038&rendertype=figure&id=A1041 FGF receptors are paired proteins on the cell surface with an internal tyrosine kinase domain]

===Dorsoventral Axis===
* Important for patterning muscles - ventral muscles - flexors; Dorsal muscles - extensors
* Early grafting experiments showed that the D/V signalling centre resided in the dorsal ectoderm
* Wnt7a is a diffusible morphogen that is secreted by dorsal ectoderm cells
* Wnt7a induces the expression of the homeobox gene Lmx1 in the underlying mesoderm adjacent to the dorsal surface
* The homeobox gene Engrailed (En1) is expressed in the opposite ventral ectoderm

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3968&rendertype=figure&id=A3969 Consequence of Wnt7a deficiency in the mouse forelimb]

===== Morphogen production from the dorsal ectoderm - Wnt7a=====
* name was derived from 'wingless' and 'int’
* Wnt gene first defined as a protooncogene, int1
* Humans have 19 Wnt genes
* Wnt7a gene is at 3p25 encoding a 349aa secreted glycoprotein
* patterning switch with different roles in different tissues
* One WNT receptor is called Frizzled (FZD) - named after a drosophila phenotype
* Frizzled gene family encodes a G protein-coupled receptor with 7 transmembrane domains

===Anteroposterior Axis===
* Zone of polarizing activity (ZPA)
* a mesenchymal posterior region of limb
* secretes sonic hedgehog (SHH)

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3792&rendertype=figure&id=A3815 ZPA secretes SHH and determines the anteroposterior axis of the limb bud]

=====Morphogen production from the ZPA - Sonic Hedgehog (SHH)=====

* Sonic hedgehog (SHH) is a diffusible morphogen secreted from cells, the protein product of the SHH gene
* The protein is processed by cleavage of the preprotein and addition of a palmitate molecule to the amino terminus and cholesterol to the carboxy terminus
* The SHH receptor is a cell surface protein called Patched which interacts with another cell surface protein Smoothened.
* Binding of SHH to Patched blocks its inhibitory effect on Smoothened and allows it to initiate an intracellular signaling cascade

===The Time Axis - Dynamic development and temporal gene expression===

* Different Hox genes are expressed at different times in the developing limb bud and pattern the fine structure of the limb.
* Structures are determined in a proximal>distal direction with time, i.e. proximal structures such as the humerus bone are laid down first.

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3941&rendertype=figure&id=A3956 Hox genes and dynamic patterning of the limb]

==Cellular origins of the limb==

===Limb cartilage and bone===
* Derived from local proliferating mesenchyme derived from the somatic lateral plate mesoderm (somatopleure)
* BMP2 and BMP4 play crucial roles in the development of cartilage - sufficient BMP must be present to achieve chondrogenesis. However, the main role is in later bone formation. Loss of BMP2 and 4 leads to a severe impairment of osteogenesis

[[Image:Mesoderm cartoon4.gif]]

[http://www.ncbi.nlm.nih.gov/books/NBK10085/figure/A3468/?report=objectonly - Differentiation of somitic mesoderm in the chick embryo]

===Limb muscle and dermis===
* Skeletal muscle derived from somites, the hypaxial part of the myotome
* Pax3 positive migratory myoblasts invade the limb bud
* Similarly, dermal cells also invade derived from the dermomyotome
* Both maintain the identity of the somite from which they were derived so that innervation corresponds to the same spinal nerve root.
* Note that dermatomes are rotated due to embryonic limb rotations

Origin of limb muscle cells - Migrations traced by grafting cells from a quail embryo into a chick embryo
* two species very similar in development
* quail cells recognizable by distinctive nucleoli
* Quail somite cells substituted for somite cells of 2 day chick embryo
* wing of chick sectioned a week later
* found muscle cells in chick wing derive from transplanted quail somites

Dorsal/Ventral Muscle Mass - sometimes referred to as the anterior and posterior muscle compartments. The posterior compartment of the lower hindlimb is mainly made up of the gastrocnemius muscles, the plantaris muscle and the soleus muscle.

Forelimb Muscles

Limb Muscle - Differentiation of Skeletal muscle is the same as in the myotome blocks but involves an extra migratory step

# Muscle precursor cells migrate to the muscle location
# Form beds of proliferating myoblasts
# Myoblasts fuse together to form a syncitial structure called a myotube
# Myotubes begin to express contractile proteins, form sarcomeres
# mature into myofibers with tendon connections at each end, motor and sensory innervation.

==Hand and Footplates==
[[File:BMP syndactyly.jpg|thumb|Depletion of BMP Signaling Causes Interdigital Syndactyly]]
* 5th week- hand and footplates appear at the ends of limb buds and ridges form digital rays
* Cells between the digital rays are removed by programmed cell death (apoptosis)
* 3-5 day difference between hand and foot development

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb024.htm hand growth]

===Apoptosis===

[http://php.med.unsw.edu.au/cellbiology/index.php?title=2009_Lecture_18 Cell Biology - Apoptosis Lecture]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3245&rendertype=figure&id=A3246 Fluorescent staining of cells undergoing apoptosis in the limb]

==Limb Rotation==
[[File:Stage20-23 limbs a.jpg|thumb]]
* 8th week limbs rotate in different directions (Humans Stage 20-23)
* thumb and toe rostral
* knee and elbow face outward
* '''upper limb rotates dorsally'''
* '''lower limb rotates ventrally'''

==Limb Innervation==
[[File:Gray0807.gif|thumb|brachial plexus]]
[[File:Dermatomes.png|thumb|Adult Dermatomes]]
* spinal cord segmental nerves form a plexus adjacent to each limb
* Brachial (upper) lumbar (lower)
* Plexus forms as nerves invade the limb bud mesechyme
* Fetal period - touch pads become visible on hands and feet

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb019.htm brachial plexus origin]

==Limb Abnormalities==

===Congenital Hip Dislocation===
[[File:Congenital dislocation hip.jpg|thumb|Congenital Hip Dislocation]]
* Instability of the femoral head in the acetabulum - ligaments may stretch: 1:60 at birth
* congenital instability of hip, later dislocates by muscle pulls or gravity
* familial predisposition female predominance
* Growth of femoral head, acetabulum and innominate bone are delayed until the femoral head fits firmly into the acetabulum

[http://embryology.med.unsw.edu.au/Notes/skmus72.htm limb abnormalities]

===Maternal===
* thalidomide Phocomelia
* short ill-formed upper or lower limbs
* hyperthermia

===Genetic===
* Trisomy 21 - Downs syndrome [[File:Trisomy21_hand.jpg|thumb]]
* Human Gene Mutations - mutation of any of the patterning genes will result in limb abnormalities
Type II syndactyly- HoxD13

===Muscle Development===
Duchenne Muscular Dystrophy
* X-linked dystrophy
* large gene encoding cytoskeletal protein- Dystrophin
* progressive wasting of muscle, die late teens

Becker Muscular Dystrophy
* milder form, adult onset

==Online Links==
* UNSW Embryology [http://embryology.med.unsw.edu.au/Notes/skmus7.htm Limb Development]
* Embryo Images [http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimbtoc.htm Limb Unit]
* International J. Dev. Biology Vol 46 [http://www.ijdb.ehu.es/0207contents.htm Special Issue- Limb Development 2002]
* Research Labs - [http://pages.unibas.ch/anatomie/zeller/seiten/seite1.html Rolf Zeller University of Basel Medical School]

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West -

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3928 Formation of the Limb Bud] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3941 Generating the Proximal-Distal Axis of the Limb]

* '''Molecular Biology of the Cell''' Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=limb_development&rid=mboc4.figgrp.3815 Figure 21-13. Sonic hedgehog as a morphogen in chick limb development]

* '''Madame Curie Bioscience Database''' Chapters taken from the Madame Curie Bioscience Database (formerly, Eurekah Bioscience Database)

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=limb_development limb development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=limb_development limb development]

==Images==
===Stage13===
[[File:Stage13 bf1c.jpg]] [[File:Stage13 sem1c.jpg]]
===Stage14===
[[File:Stage14_bf2cl.jpg]] [[File:Stage14_sem1c.jpg]]

{{Glossary}}
{{Footer}}

Lecture - Limb Development

2013-09-16T07:24:56Z

Z3283213:

==Introduction==
[[File:Appendicular skeleton.jpg|thumb|400px]]
This lecture is an introduction to the events in limb development. Cells of the ectoderm, cells derived from the dermatome and the hypaxial portion of the myotome mix with somatic component of the lateral plate mesoderm to give rise to the fore and hind limbs.

The appendicular skeleton consists of: Shoulder girdle, Upper limb (arm, hand), Pelvic girdle, Lower limb (leg, foot).

[[:File:Human_Carnegie_stage_1-23.jpg|Carnegie stage 1-23]]

==Lecture Objectives==
[[File:Stage14 sem2b-limb.jpg|thumb|Human Embryo stage 14 SEM]]

*Timing and location of limb bud development
*The tissues from which limb buds are made
*Determining the position of the limb buds on the body axis
*Signaling control mechanisms of early limb bud formation
*The control of forelimb and hindlimb specification
*Controlling the patterning of the limbs in 3 axes
*Rotation of the limbs and consequences for skin and innervation
*Shaping the hand and footplates through apoptosis

==Information==

Lecture Date: 2013-09-17 Lecture Time: 16:00 Venue: BioMed E Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Limb_development.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (chapter links only work with a UNSW connection).
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00016-3&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00016-3 Chapter 16 – Development of Limbs]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (chapter links only work with a UNSW connection).

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10018-1 Chapter 18 - Development of the Limbs]
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

* [[Musculoskeletal System - Limb Development|Limb Development]]
* [[Musculoskeletal System - Limb Abnormalities|Limb Abnormalities]]
* '''Developmental Dynamics''' - Special Issue: [http://onlinelibrary.wiley.com/doi/10.1002/dvdy.v240.5/issuetoc Special Issue on Limb Development] May 2011 Volume 240, Issue 5
|}

:'''Links:''' [[Embryology_Textbooks_-_UNSW|UNSW Textbooks]] | [[Embryology Textbooks]]

==Limb Buds==
* Limbs are initially undifferentiated mesenchyme (mesoderm) with an epithelial (ectoderm) covering. Uniform paddle shaped structures that grow outwards gradually.
* One the first noticeable changes is the development of a large blood vessel (marginal vein) which runs just underneath a thickening of the ectoderm at the tip of the limb bud called the Apical Ectodermal Ridge (AER).
* Positioning of the limbs is distant from final location

==Upper and Lower Limb==
[[File:Stage20-23 limbs.jpg|600px]]
[[File:Stage14_somites_limbbuds.png|thumb]]
Limb development occurs at different times for forelimbs and hindlimbs. In the mid-4th week, human upper limb buds first form and lower limbs about 2 days later. The limbs form at vertebra segmental levels C5-C8 (upper limbs) L3-L5 (lower limbs).

==Limb Axis Formation==

Four Concepts - much of the work has been carried out using the chicken and more recently the mouse model of development.

# Limb Initiation
# Proximodistal Axis
# Dorsoventral Axis
# Anteroposterior Axis

===Limb Initiation===
* Fibroblast growth factor (FGF) coated beads can induce additional limb
* FGF10 is expressed in lateral plate mesoderm prior to bud formation induces expression of FGF8 in the overlying ectoderm. FGF8 induces continued growth in the underlying mesoderm - thus a positive feedback loop
* Anterior boundary of Hoxc6 expression coincides with the position of forelimb development

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3941&rendertype=figure&id=A3953 Autoregulatory loop of induction between FGF10 and FGF8]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A1038&rendertype=figure&id=A1041 Site of FGF10 expression in the chick embryo]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3881 Positioning of the limb on the rostrocaudal (anteroposterior) axis is determined by the expression of Hox genes]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3882 Examples of Hox gene expression boundaries in the mouse Hoxb2 and Hoxb4]

===Limb Identity===

Forelimb and hindlimb (mouse) identity appears to be regulated by T-box (Tbx) genes, which are a family of transcription factors.
* hindlimb Tbx4 is expressed.
* forelimb Tbx5 is expressed.
* Tbx2 and Tbx3 are expressed in both limbs.

'''Related Research''' - [http://www.ncbi.nlm.nih.gov/pubmed/12490567?dopt=Abstract PMID: 12490567] | [http://dev.biologists.org/cgi/content/figsonly/130/3/623 Development 2003 Figures] | [http://dev.biologists.org/cgi/content/full/130/3/623/FIG1 Scanning electron micrographs of E9 Limb bud wild-type and Tbx5del/del] [http://dev.biologists.org/cgi/content/full/130/3/623/FIG7 A model for early stages of limb bud growth] | [http://www.ncbi.nlm.nih.gov/pubmed/12736217?dopt=Abstract PMID: 12736217] | [http://dev.biologists.org/cgi/content/figsonly/130/12/2741 Development 2003 Figures]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3928&rendertype=figure&id=A3936 Tbx4 expression can turn an experimentally induced forelimb into a hindlimb]

==Axes and Morphogens==
[[File:Limb bud geometry and patterning.jpg|thumb|Limb bud geometry and patterning]]
* '''Anteroposterior''' - (Rostrocaudal, Craniocaudal, Cephalocaudal) from the head end to opposite end of body or tail.
* '''Dorsoventral''' - from the spinal column (back) to belly (front).
* '''Proximodistal''' - from the tip of an appendage (distal) to where it joins the body (proximal).

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3885&rendertype=figure&id=A3902 Model of patterning signals in the vertebrate limb]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3792&rendertype=figure&id=A3812 Diffusible morphogens create a concentration gradient accross an embryonic field]

===Proximodistal Axis===
* Apical Ectodermal Ridge (AER) initially formed at the site of FGF10 induction
* then AER secretes FGF8 and FGF4 slightly later
* FGFs stimulate proliferation and outgrowth in the underlying mesenchyme

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb017.htm limb development at embryo images online]

=====Morphogen production from the AER - The Fibroblast Growth Factors (FGFs)=====
* 22 FGF genes identified in humans
* bind membrane tyrosine kinase receptors
* Patterning switch with many different roles in different tissues

FGF receptors
* comprise a family of at least 4 related but individually distinct tyrosine kinase receptors (FGFR1- 4) similar protein structure
* 3 immunoglobulin-like domains in extracellular region
* single membrane spanning segment
* cytoplasmic tyrosine kinase domain

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A1038&rendertype=figure&id=A1041 FGF receptors are paired proteins on the cell surface with an internal tyrosine kinase domain]

===Dorsoventral Axis===
* Important for patterning muscles - ventral muscles - flexors; Dorsal muscles - extensors
* Early grafting experiments showed that the D/V signalling centre resided in the dorsal ectoderm
* Wnt7a is a diffusible morphogen that is secreted by dorsal ectoderm cells
* Wnt7a induces the expression of the homeobox gene Lmx1 in the underlying mesoderm adjacent to the dorsal surface
* The homeobox gene Engrailed (En1) is expressed in the opposite ventral ectoderm

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3968&rendertype=figure&id=A3969 Consequence of Wnt7a deficiency in the mouse forelimb]

===== Morphogen production from the dorsal ectoderm - Wnt7a=====
* name was derived from 'wingless' and 'int’
* Wnt gene first defined as a protooncogene, int1
* Humans have 19 Wnt genes
* Wnt7a gene is at 3p25 encoding a 349aa secreted glycoprotein
* patterning switch with different roles in different tissues
* One WNT receptor is called Frizzled (FZD) - named after a drosophila phenotype
* Frizzled gene family encodes a G protein-coupled receptor with 7 transmembrane domains

===Anteroposterior Axis===
* Zone of polarizing activity (ZPA)
* a mesenchymal posterior region of limb
* secretes sonic hedgehog (SHH)

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3792&rendertype=figure&id=A3815 ZPA secretes SHH and determines the anteroposterior axis of the limb bud]

=====Morphogen production from the ZPA - Sonic Hedgehog (SHH)=====

* Sonic hedgehog (SHH) is a diffusible morphogen secreted from cells, the protein product of the SHH gene
* The protein is processed by cleavage of the preprotein and addition of a palmitate molecule to the amino terminus and cholesterol to the carboxy terminus
* The SHH receptor is a cell surface protein called Patched which interacts with another cell surface protein Smoothened.
* Binding of SHH to Patched blocks its inhibitory effect on Smoothened and allows it to initiate an intracellular signaling cascade

===The Time Axis - Dynamic development and temporal gene expression===

* Different Hox genes are expressed at different times in the developing limb bud and pattern the fine structure of the limb.
* Structures are determined in a proximal>distal direction with time, i.e. proximal structures such as the humerus bone are laid down first.

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3941&rendertype=figure&id=A3956 Hox genes and dynamic patterning of the limb]

==Cellular origins of the limb==

===Limb cartilage and bone===
* Derived from local proliferating mesenchyme derived from the somatic lateral plate mesoderm (somatopleure)
* BMP2 and BMP4 play crucial roles in the development of cartilage - sufficient BMP must be present to achieve chondrogenesis. However, the main role is in later bone formation. Loss of BMP2 and 4 leads to a severe impairment of osteogenesis

[[Image:Mesoderm cartoon4.gif]]

[http://www.ncbi.nlm.nih.gov/books/NBK10085/figure/A3468/?report=objectonly - Differentiation of somitic mesoderm in the chick embryo]

===Limb muscle and dermis===
* Skeletal muscle derived from somites, the hypaxial part of the myotome
* Pax3 positive migratory myoblasts invade the limb bud
* Similarly, dermal cells also invade derived from the dermomyotome
* Both maintain the identity of the somite from which they were derived so that innervation corresponds to the same spinal nerve root.
* Note that dermatomes are rotated due to embryonic limb rotations

Origin of limb muscle cells - Migrations traced by grafting cells from a quail embryo into a chick embryo
* two species very similar in development
* quail cells recognizable by distinctive nucleoli
* Quail somite cells substituted for somite cells of 2 day chick embryo
* wing of chick sectioned a week later
* found muscle cells in chick wing derive from transplanted quail somites

Dorsal/Ventral Muscle Mass - sometimes referred to as the anterior and posterior muscle compartments. The posterior compartment of the lower hindlimb is mainly made up of the gastrocnemius muscles, the plantaris muscle and the soleus muscle.

Forelimb Muscles

Limb Muscle - Differentiation of Skeletal muscle is the same as in the myotome blocks but involves an extra migratory step

# Muscle precursor cells migrate to the muscle location
# Form beds of proliferating myoblasts
# Myoblasts fuse together to form a syncitial structure called a myotube
# Myotubes begin to express contractile proteins, form sarcomeres
# mature into myofibers with tendon connections at each end, motor and sensory innervation.

==Hand and Footplates==
[[File:BMP syndactyly.jpg|thumb|Depletion of BMP Signaling Causes Interdigital Syndactyly]]
* 5th week- hand and footplates appear at the ends of limb buds and ridges form digital rays
* Cells between the digital rays are removed by programmed cell death (apoptosis)
* 3-5 day difference between hand and foot development

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb024.htm hand growth]

===Apoptosis===

[http://php.med.unsw.edu.au/cellbiology/index.php?title=2009_Lecture_18 Cell Biology - Apoptosis Lecture]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3245&rendertype=figure&id=A3246 Fluorescent staining of cells undergoing apoptosis in the limb]

==Limb Rotation==
[[File:Stage20-23 limbs a.jpg|thumb]]
* 8th week limbs rotate in different directions (Humans Stage 20-23)
* thumb and toe rostral
* knee and elbow face outward
* '''upper limb rotates dorsally'''
* '''lower limb rotates ventrally'''

==Limb Innervation==
[[File:Gray0807.gif|thumb|brachial plexus]]
[[File:Dermatomes.png|thumb|Adult Dermatomes]]
* spinal cord segmental nerves form a plexus adjacent to each limb
* Brachial (upper) lumbar (lower)
* Plexus forms as nerves invade the limb bud mesechyme
* Fetal period - touch pads become visible on hands and feet

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb019.htm brachial plexus origin]

==Limb Abnormalities==

===Congenital Hip Dislocation===
[[File:Congenital dislocation hip.jpg|thumb|Congenital Hip Dislocation]]
* Instability of the femoral head in the acetabulum - ligaments may stretch: 1:60 at birth
* congenital instability of hip, later dislocates by muscle pulls or gravity
* familial predisposition female predominance
* Growth of femoral head, acetabulum and innominate bone are delayed until the femoral head fits firmly into the acetabulum

[http://embryology.med.unsw.edu.au/Notes/skmus72.htm limb abnormalities]

===Maternal===
* thalidomide Phocomelia
* short ill-formed upper or lower limbs
* hyperthermia

===Genetic===
* Trisomy 21 - Downs syndrome [[File:Trisomy21_hand.jpg|thumb]]
* Human Gene Mutations - mutation of any of the patterning genes will result in limb abnormalities
Type II syndactyly- HoxD13

===Muscle Development===
Duchenne Muscular Dystrophy
* X-linked dystrophy
* large gene encoding cytoskeletal protein- Dystrophin
* progressive wasting of muscle, die late teens

Becker Muscular Dystrophy
* milder form, adult onset

==Online Links==
* UNSW Embryology [http://embryology.med.unsw.edu.au/Notes/skmus7.htm Limb Development]
* Embryo Images [http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimbtoc.htm Limb Unit]
* International J. Dev. Biology Vol 46 [http://www.ijdb.ehu.es/0207contents.htm Special Issue- Limb Development 2002]
* Research Labs - [http://pages.unibas.ch/anatomie/zeller/seiten/seite1.html Rolf Zeller University of Basel Medical School]

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West -

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3928 Formation of the Limb Bud] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3941 Generating the Proximal-Distal Axis of the Limb]

* '''Molecular Biology of the Cell''' Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=limb_development&rid=mboc4.figgrp.3815 Figure 21-13. Sonic hedgehog as a morphogen in chick limb development]

* '''Madame Curie Bioscience Database''' Chapters taken from the Madame Curie Bioscience Database (formerly, Eurekah Bioscience Database)

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=limb_development limb development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=limb_development limb development]

==Images==
===Stage13===
[[File:Stage13 bf1c.jpg]] [[File:Stage13 sem1c.jpg]]
===Stage14===
[[File:Stage14_bf2cl.jpg]] [[File:Stage14_sem1c.jpg]]

{{Glossary}}
{{Footer}}

Lecture - Limb Development

2013-09-16T07:22:36Z

Z3283213:

==Introduction==
[[File:Appendicular skeleton.jpg|thumb|400px]]
This lecture is an introduction to the events in limb development. Cells of the ectoderm, cells derived from the dermatome and the hypaxial portion of the myotome mix with somatic component of the lateral plate mesoderm to give rise to the fore and hind limbs.

The appendicular skeleton consists of: Shoulder girdle, Upper limb (arm, hand), Pelvic girdle, Lower limb (leg, foot).

[[:File:Human_Carnegie_stage_1-23.jpg|Carnegie stage 1-23]]

==Lecture Objectives==
[[File:Stage14 sem2b-limb.jpg|thumb|Human Embryo stage 14 SEM]]

* Understanding of limb positioning
* Understanding of differences in developmental timing of upper and lower limbs
* Understanding of limb patterning - regions and factors determining the limb axes
* Understanding of limb rotation
* Understanding of limb muscle, blood vessel, bone and nerve formation
* Brief understanding of limb molecular factors and cell death
* Brief understanding of limb abnormalities

==Information==

Lecture Date: 2013-09-17 Lecture Time: 16:00 Venue: BioMed E Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Limb_development.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (chapter links only work with a UNSW connection).
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00016-3&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00016-3 Chapter 16 – Development of Limbs]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (chapter links only work with a UNSW connection).

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10018-1 Chapter 18 - Development of the Limbs]
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

* [[Musculoskeletal System - Limb Development|Limb Development]]
* [[Musculoskeletal System - Limb Abnormalities|Limb Abnormalities]]
* '''Developmental Dynamics''' - Special Issue: [http://onlinelibrary.wiley.com/doi/10.1002/dvdy.v240.5/issuetoc Special Issue on Limb Development] May 2011 Volume 240, Issue 5
|}

:'''Links:''' [[Embryology_Textbooks_-_UNSW|UNSW Textbooks]] | [[Embryology Textbooks]]

==Limb Buds==
* Limbs are initially undifferentiated mesenchyme (mesoderm) with an epithelial (ectoderm) covering. Uniform paddle shaped structures that grow outwards gradually.
* One the first noticeable changes is the development of a large blood vessel (marginal vein) which runs just underneath a thickening of the ectoderm at the tip of the limb bud called the Apical Ectodermal Ridge (AER).
* Positioning of the limbs is distant from final location

==Upper and Lower Limb==
[[File:Stage20-23 limbs.jpg|600px]]
[[File:Stage14_somites_limbbuds.png|thumb]]
Limb development occurs at different times for forelimbs and hindlimbs. In the mid-4th week, human upper limb buds first form and lower limbs about 2 days later. The limbs form at vertebra segmental levels C5-C8 (upper limbs) L3-L5 (lower limbs).

==Limb Axis Formation==

Four Concepts - much of the work has been carried out using the chicken and more recently the mouse model of development.

# Limb Initiation
# Proximodistal Axis
# Dorsoventral Axis
# Anteroposterior Axis

===Limb Initiation===
* Fibroblast growth factor (FGF) coated beads can induce additional limb
* FGF10 is expressed in lateral plate mesoderm prior to bud formation induces expression of FGF8 in the overlying ectoderm. FGF8 induces continued growth in the underlying mesoderm - thus a positive feedback loop
* Anterior boundary of Hoxc6 expression coincides with the position of forelimb development

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3941&rendertype=figure&id=A3953 Autoregulatory loop of induction between FGF10 and FGF8]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A1038&rendertype=figure&id=A1041 Site of FGF10 expression in the chick embryo]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3881 Positioning of the limb on the rostrocaudal (anteroposterior) axis is determined by the expression of Hox genes]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3882 Examples of Hox gene expression boundaries in the mouse Hoxb2 and Hoxb4]

===Limb Identity===

Forelimb and hindlimb (mouse) identity appears to be regulated by T-box (Tbx) genes, which are a family of transcription factors.
* hindlimb Tbx4 is expressed.
* forelimb Tbx5 is expressed.
* Tbx2 and Tbx3 are expressed in both limbs.

'''Related Research''' - [http://www.ncbi.nlm.nih.gov/pubmed/12490567?dopt=Abstract PMID: 12490567] | [http://dev.biologists.org/cgi/content/figsonly/130/3/623 Development 2003 Figures] | [http://dev.biologists.org/cgi/content/full/130/3/623/FIG1 Scanning electron micrographs of E9 Limb bud wild-type and Tbx5del/del] [http://dev.biologists.org/cgi/content/full/130/3/623/FIG7 A model for early stages of limb bud growth] | [http://www.ncbi.nlm.nih.gov/pubmed/12736217?dopt=Abstract PMID: 12736217] | [http://dev.biologists.org/cgi/content/figsonly/130/12/2741 Development 2003 Figures]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3928&rendertype=figure&id=A3936 Tbx4 expression can turn an experimentally induced forelimb into a hindlimb]

==Axes and Morphogens==
[[File:Limb bud geometry and patterning.jpg|thumb|Limb bud geometry and patterning]]
* '''Anteroposterior''' - (Rostrocaudal, Craniocaudal, Cephalocaudal) from the head end to opposite end of body or tail.
* '''Dorsoventral''' - from the spinal column (back) to belly (front).
* '''Proximodistal''' - from the tip of an appendage (distal) to where it joins the body (proximal).

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3885&rendertype=figure&id=A3902 Model of patterning signals in the vertebrate limb]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3792&rendertype=figure&id=A3812 Diffusible morphogens create a concentration gradient accross an embryonic field]

===Proximodistal Axis===
* Apical Ectodermal Ridge (AER) initially formed at the site of FGF10 induction
* then AER secretes FGF8 and FGF4 slightly later
* FGFs stimulate proliferation and outgrowth in the underlying mesenchyme

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb017.htm limb development at embryo images online]

=====Morphogen production from the AER - The Fibroblast Growth Factors (FGFs)=====
* 22 FGF genes identified in humans
* bind membrane tyrosine kinase receptors
* Patterning switch with many different roles in different tissues

FGF receptors
* comprise a family of at least 4 related but individually distinct tyrosine kinase receptors (FGFR1- 4) similar protein structure
* 3 immunoglobulin-like domains in extracellular region
* single membrane spanning segment
* cytoplasmic tyrosine kinase domain

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A1038&rendertype=figure&id=A1041 FGF receptors are paired proteins on the cell surface with an internal tyrosine kinase domain]

===Dorsoventral Axis===
* Important for patterning muscles - ventral muscles - flexors; Dorsal muscles - extensors
* Early grafting experiments showed that the D/V signalling centre resided in the dorsal ectoderm
* Wnt7a is a diffusible morphogen that is secreted by dorsal ectoderm cells
* Wnt7a induces the expression of the homeobox gene Lmx1 in the underlying mesoderm adjacent to the dorsal surface
* The homeobox gene Engrailed (En1) is expressed in the opposite ventral ectoderm

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3968&rendertype=figure&id=A3969 Consequence of Wnt7a deficiency in the mouse forelimb]

===== Morphogen production from the dorsal ectoderm - Wnt7a=====
* name was derived from 'wingless' and 'int’
* Wnt gene first defined as a protooncogene, int1
* Humans have 19 Wnt genes
* Wnt7a gene is at 3p25 encoding a 349aa secreted glycoprotein
* patterning switch with different roles in different tissues
* One WNT receptor is called Frizzled (FZD) - named after a drosophila phenotype
* Frizzled gene family encodes a G protein-coupled receptor with 7 transmembrane domains

===Anteroposterior Axis===
* Zone of polarizing activity (ZPA)
* a mesenchymal posterior region of limb
* secretes sonic hedgehog (SHH)

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3792&rendertype=figure&id=A3815 ZPA secretes SHH and determines the anteroposterior axis of the limb bud]

=====Morphogen production from the ZPA - Sonic Hedgehog (SHH)=====

* Sonic hedgehog (SHH) is a diffusible morphogen secreted from cells, the protein product of the SHH gene
* The protein is processed by cleavage of the preprotein and addition of a palmitate molecule to the amino terminus and cholesterol to the carboxy terminus
* The SHH receptor is a cell surface protein called Patched which interacts with another cell surface protein Smoothened.
* Binding of SHH to Patched blocks its inhibitory effect on Smoothened and allows it to initiate an intracellular signaling cascade

===The Time Axis - Dynamic development and temporal gene expression===

* Different Hox genes are expressed at different times in the developing limb bud and pattern the fine structure of the limb.
* Structures are determined in a proximal>distal direction with time, i.e. proximal structures such as the humerus bone are laid down first.

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3941&rendertype=figure&id=A3956 Hox genes and dynamic patterning of the limb]

==Cellular origins of the limb==

===Limb cartilage and bone===
* Derived from local proliferating mesenchyme derived from the somatic lateral plate mesoderm (somatopleure)
* BMP2 and BMP4 play crucial roles in the development of cartilage - sufficient BMP must be present to achieve chondrogenesis. However, the main role is in later bone formation. Loss of BMP2 and 4 leads to a severe impairment of osteogenesis

[[Image:Mesoderm cartoon4.gif]]

[http://www.ncbi.nlm.nih.gov/books/NBK10085/figure/A3468/?report=objectonly - Differentiation of somitic mesoderm in the chick embryo]

===Limb muscle and dermis===
* Skeletal muscle derived from somites, the hypaxial part of the myotome
* Pax3 positive migratory myoblasts invade the limb bud
* Similarly, dermal cells also invade derived from the dermomyotome
* Both maintain the identity of the somite from which they were derived so that innervation corresponds to the same spinal nerve root.
* Note that dermatomes are rotated due to embryonic limb rotations

Origin of limb muscle cells - Migrations traced by grafting cells from a quail embryo into a chick embryo
* two species very similar in development
* quail cells recognizable by distinctive nucleoli
* Quail somite cells substituted for somite cells of 2 day chick embryo
* wing of chick sectioned a week later
* found muscle cells in chick wing derive from transplanted quail somites

Dorsal/Ventral Muscle Mass - sometimes referred to as the anterior and posterior muscle compartments. The posterior compartment of the lower hindlimb is mainly made up of the gastrocnemius muscles, the plantaris muscle and the soleus muscle.

Forelimb Muscles

Limb Muscle - Differentiation of Skeletal muscle is the same as in the myotome blocks but involves an extra migratory step

# Muscle precursor cells migrate to the muscle location
# Form beds of proliferating myoblasts
# Myoblasts fuse together to form a syncitial structure called a myotube
# Myotubes begin to express contractile proteins, form sarcomeres
# mature into myofibers with tendon connections at each end, motor and sensory innervation.

==Hand and Footplates==
[[File:BMP syndactyly.jpg|thumb|Depletion of BMP Signaling Causes Interdigital Syndactyly]]
* 5th week- hand and footplates appear at the ends of limb buds and ridges form digital rays
* Cells between the digital rays are removed by programmed cell death (apoptosis)
* 3-5 day difference between hand and foot development

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb024.htm hand growth]

===Apoptosis===

[http://php.med.unsw.edu.au/cellbiology/index.php?title=2009_Lecture_18 Cell Biology - Apoptosis Lecture]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3245&rendertype=figure&id=A3246 Fluorescent staining of cells undergoing apoptosis in the limb]

==Limb Rotation==
[[File:Stage20-23 limbs a.jpg|thumb]]
* 8th week limbs rotate in different directions (Humans Stage 20-23)
* thumb and toe rostral
* knee and elbow face outward
* '''upper limb rotates dorsally'''
* '''lower limb rotates ventrally'''

==Limb Innervation==
[[File:Gray0807.gif|thumb|brachial plexus]]
[[File:Dermatomes.png|thumb|Adult Dermatomes]]
* spinal cord segmental nerves form a plexus adjacent to each limb
* Brachial (upper) lumbar (lower)
* Plexus forms as nerves invade the limb bud mesechyme
* Fetal period - touch pads become visible on hands and feet

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb019.htm brachial plexus origin]

==Limb Abnormalities==

===Congenital Hip Dislocation===
[[File:Congenital dislocation hip.jpg|thumb|Congenital Hip Dislocation]]
* Instability of the femoral head in the acetabulum - ligaments may stretch: 1:60 at birth
* congenital instability of hip, later dislocates by muscle pulls or gravity
* familial predisposition female predominance
* Growth of femoral head, acetabulum and innominate bone are delayed until the femoral head fits firmly into the acetabulum

[http://embryology.med.unsw.edu.au/Notes/skmus72.htm limb abnormalities]

===Maternal===
* thalidomide Phocomelia
* short ill-formed upper or lower limbs
* hyperthermia

===Genetic===
* Trisomy 21 - Downs syndrome [[File:Trisomy21_hand.jpg|thumb]]
* Human Gene Mutations - mutation of any of the patterning genes will result in limb abnormalities
Type II syndactyly- HoxD13

===Muscle Development===
Duchenne Muscular Dystrophy
* X-linked dystrophy
* large gene encoding cytoskeletal protein- Dystrophin
* progressive wasting of muscle, die late teens

Becker Muscular Dystrophy
* milder form, adult onset

==Online Links==
* UNSW Embryology [http://embryology.med.unsw.edu.au/Notes/skmus7.htm Limb Development]
* Embryo Images [http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimbtoc.htm Limb Unit]
* International J. Dev. Biology Vol 46 [http://www.ijdb.ehu.es/0207contents.htm Special Issue- Limb Development 2002]
* Research Labs - [http://pages.unibas.ch/anatomie/zeller/seiten/seite1.html Rolf Zeller University of Basel Medical School]

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West -

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3928 Formation of the Limb Bud] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3941 Generating the Proximal-Distal Axis of the Limb]

* '''Molecular Biology of the Cell''' Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=limb_development&rid=mboc4.figgrp.3815 Figure 21-13. Sonic hedgehog as a morphogen in chick limb development]

* '''Madame Curie Bioscience Database''' Chapters taken from the Madame Curie Bioscience Database (formerly, Eurekah Bioscience Database)

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=limb_development limb development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=limb_development limb development]

==Images==
===Stage13===
[[File:Stage13 bf1c.jpg]] [[File:Stage13 sem1c.jpg]]
===Stage14===
[[File:Stage14_bf2cl.jpg]] [[File:Stage14_sem1c.jpg]]

{{Glossary}}
{{Footer}}

Lecture - Musculoskeletal Development

2013-09-16T07:20:38Z

Z3283213:

== Introduction ==
[[File:Axial skeleton.jpg|thumb|400px]]
This lecture is an introduction to the process of musculoskeletal development. In the body, this is mainly about '''mesoderm''' differentiation beginning with an embryonic connective tissue structure, the '''mesenchyme'''. In the head, this is a mixture of mesoderm and neural crest differentiation, from mesenchyme and ectomesenchyme respectively. The lecture will cover mainly cartilage and bone, as muscle will be covered in the limb lecture and in this week's laboratory.

Note that genes that control skeleton patterning and cell differentiation are different.

==Lecture Objectives==
[[File:Stage14_sem1c.jpg|thumb|Embryo stage 14 SEM]]

* Understanding of mesoderm and neural crest development.
* Understanding of connective tissue development.
* Understanding of muscle, cartilage and bone development.
* Understanding of the two forms of bone development.
* Brief understanding of bone molecular development.
* Brief understanding of other bone roles.
* Brief understanding of bone abnormalities.

==Information==

Lecture Date: 2013-09-17 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Musculoskeletal.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00014-X&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00014-X Chapter 14 - Skeletal System]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00015-1&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00015-1 Chapter 15 - Muscular System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009.

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10008-9 Chapter 8 - Development of the Musculoskeletal System]
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Musculoskeletal Links}}
|}

:'''Links:''' [[Embryology_Textbooks_-_UNSW|UNSW Textbooks]] | [[Embryology Textbooks]]

==Musculoskeletal medical conditions==

[http://www.aihw.gov.au/publications/index.cfm/title/10699 Health expenditure for arthritis and musculoskeletal conditions, 2004-05]

:"Arthritis and musculoskeletal conditions affect more than 6 million Australians. In 2004-05, direct health expenditure on these conditions amounted to $4.0 billion or 7.5% of total allocated health expenditure in Australia."

[http://geneticsf.labanca.net/?p=771 Craniofacial abnormalities in Williams-Beuren syndrome]

Williams-Beuren syndrome is a genetic disease caused by a hemizygous deletion of 28 genes on chromosome 7. Leads to a distinctive set of craniofacial features. Probably caused by defects in patterning rather than differentiation as all of the structures form normally, just in slightly different positions relative to each other.
[http://www.med.unsw.edu.au/SOMSWeb.nsf/page/Neuromuscular%20and%20Regenerative%20Medicine%20Unit Neuromuscular and regenerative medicine unit, SOMS]

==Anterior-Posterior (A/P) Patterning of the axial musculoskeletal system==
[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3881 Expression of the Hox genes defines locations on the anteroposterior axis]

The hox gene clusters control anteroposterior (A/P) patterning to provide positional clues for the development of specific structures e.g. cervical, thoracic, lumbar and sacral vertebrae.

== Patterning and differentiation of the somitic mesoderm ==

[[Image:Mesoderm cartoon4.gif]]

===Sclerotome===
[[File:Somite_cartoon3.png]][[File:Somite_cartoon4.png]][[File:Somite_cartoon5.png]]

The notochord is an ancient evolutionary structure that forms a rigid A/P rod in chordate animals - chordates are ancestors of vertebrates including humans

[http://www.ncbi.nlm.nih.gov/books/NBK10085/figure/A3468/?report=objectonly - Differentiation of somitic mesoderm in the chick embryo]

==Neural Crest Derived Cells==

[http://www.ncbi.nlm.nih.gov/books/NBK10065/figure/A3111/?report=objectonly Migration and tissue contribution of neural crest cells in the chick embryo]

Neural crest-derived cells are essential to form the bones and cartilage of the face and neck, it also forms the cranial nerves and pigment cells, dorsal root ganglia and the sympathetic neurons.

==Making an Embryonic Cartilage Model==

Stage 1 - Signalling interactions between mesenchyme and an epithelial population

Stage 2 - Cell Condensation - mesenchymal dispersed cell population, gathers together to differentiate

Stage 3 - Overt Differentiation

[[File:Endochondral ossification.jpg|thumb]]
[[File:Developing vertebra.jpg|thumb]]

[http://www.mdconsult.com/books/figure.do?figure=true&eid=4-u1.0-B978-1-4160-3706-4..50017-7--f3&sectionEid=4-u1.0-B978-1-4160-3706-4..50017-7&isbn=978-1-4160-3706-4&uniqId=281144369-2 Stages of Cartilage Differentiation]

[http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Cartilage/Cartil.htm Histology - Cartilage]

===Development of Vertebrae===
[[File:Gray0082.jpg|thumb]]
* Vertebral column formation - week 4, somite sclerotome surrounds notochord.
** notochord (and floorplate) induces sclerotome migration and vertebral body cartilages.
** neural tube induces vertebral arches.
* Scleretome has 2 components
** Rostral (upper) loose and a caudal (lower) compact

[[File:Gray0065.jpg|500px]] [http://embryology.med.unsw.edu.au/Movies/mesoderm/vertabra3.mov Vertebra]
* Vertebral segmentation is shifted 1/2 somite caudally - by fusion rostral compact with caudal loose to form vertebra from 2 sclerotomes.
** This allows (i) the segmental spinal nerves to emerge between the vertebral bodies (at the same level as the intervertebral discs) (ii) the somite-derived muscle masses to interconnect between the intervertebral joints.

* Caudal dense region also forms neural arch.

Adult vertebral column
* 33 total - 7 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 5 coccygeal

====Intervertebral Disc====
* Structure - annulus and nucleus pulposus
* dense region of sclerotome.
* notochord initially contributes to nucleus pulposus of each disc, contribution replaced and lost postnatally.

====Ribs====
[[File:Gray0067.png|thumb|vertebra origin: body, arch, and costal process]]
* dense region of sclerotome contributes costal processes (thoracic region).
** chondrification commences day 45 and rib cage is cartilage by end of embryonic period.

====Sternum====

* mesenchyme from ventral body wall (manubrium, body, ziphoid).
* sternal cartilage "bars" fuse with costal processes and developing clavicles by end of embryonic period.

===Cartilage growth===
[http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Cartilage/Cartil.htm Histology - Cartilage]
* Interstitial growth - occurs mainly in immature cartilage. Chondroblasts in existing cartilage divide and form small groups of cells (isogenous groups) which produce matrix to become separated from each other by a thin partition of matrix.
* Appositional growth - occurs also in mature cartilage. Mesenchymal cells surrounding the cartilage in the deep part of the perichondrium (or the chondrogenic layer) differentiate into chondroblasts.

===Hypertrophic Chondrocytes===
* secrete VEGF, promoting vascular invasion
* hypertrophic calcified cartilage becomes resorbed, by recruited chondroclasts/osteoclasts via MMP9

== Formation of Bone ==
[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3479&rendertype=figure&id=A3482 Mice lacking Cbfa1 (Runx2) don't form bone]

[[File:Endochondral bone.jpg|300px|left]]
* Two major systems of bones: the axial skeleton and the appendicular skeleton.
** axial skeleton - 80 bones (skull, vertebrae, ribs, and sternum)
** appendicular skeleton - 126 bones (shoulders, pelvis, and limbs)

* Two main forms of bone formation: Endochondral and Intramembranous. Ossification process continues postnatally through puberty until mid 20s.

[http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Bone/Bone.htm Histology - Bone]
[[File:Periosteum.jpg|thumb]]
[[File:Gray0101.jpg|200px]][[File:Gray0118.jpg|200px]][[File:Gray0119.jpg|200px]]

===Endochondral Ossification===
[[File:Ossification endochondral 1c.jpg|thumb]]
* Majority of skeleton formed by this process (vertebra, limb long bones)
* Osteoblasts derived from the bone collar replace cartilage matrix with a matrix rich in type I collagen leading to bone formation
* Ossification centres (primary and secondary)
* Early ossification occurs at ends of long bone
[http://www.ncbi.nlm.nih.gov/books/NBK10056/figure/A3484/?report=objectonly - Diagram of ossification in long bone]
[http://www.e-radiography.net/articles/ossification/ossification.htm University of Bristol - ossification]

===Intramembranous ossification in the turtle - a model system===
[http://www.ncbi.nlm.nih.gov/books/NBK10056/figure/A3481/?report=objectonly - Intramembranous ossification]

===Intramembranous Ossification in the skull vault===
[[File:Fetal head medial.jpg|300px]][[File:Fetal head lateral.jpg|300px]]
[[File:Ossification centre.jpg|thumb]]

* Specialized form of ossification from a mesenchymal membrane. (skull and clavicle)- Neural crest-derived mesenchymal cells proliferate - some cells differentiate to form blood vessels, others become osteoblasts and begin secreting collagen-proteoglycan matrix that can bind calcium salts.

====Skull====
[[File:Human skull lateral simplified.png|thumb|skull bones]]
[[File:Fetal head section.jpg|thumb|12 week fetal head]]
The Skull is a unique skeletal structure in several ways: embryonic cellular origin (neural crest), form of ossification (intramembranous and endochondrial) and flexibility (fibrous sutures). [http://embryology.med.unsw.edu.au/Notes/skmus8a.htm Musculoskeletal Development - Skull Development]

The bones enclosing the brain have large flexible fibrous joints (sutures) which allow firstly the head to compress and pass through the birth canal and secondly to postnatally expand for brain growth.

These sutures gradually fuse at different times postnatally, firstly the metopic suture in infancy and the others much later. Abnormal fusion (synostosis) of any of the sutures will lead to a number of different skull defects.

===Osteogenesis===

* Osteoprogenitor cell - periosteum and endosteum
* Osteoblast - Secrete bone matrix, differentiate into osteocytes
* Osteocyte - Mature bone cell, Embedded in matrix, matrix calcifies soon after deposition

===Osteoclastogenesis===
* Formation of mature osteoclasts involved in bone resorption - the osteoblasts regulate this process through the production of RANKL (Receptor Activator for Nuclear Factor κ B Ligand) which is found on the cell surface of osteoblasts. RANKL is a key player in rheumatoid arthritis.

Osteoclast origin- fusion of monocytes or macrophages, Blood macrophage precursor, Attach to bone matrix - very large cells containing 15-20 nucleii.

Lysosomes - released into space between ruffled border and bone matrix, enzymes break down collagen fibres, resorption bays or Howship's lacunae

== Muscle ==
[http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Muscle/Muscle.htm Histology - Muscle]

===Myogenesis===

* Smooth muscle - cells originate from undifferentiated mesenchymal cells. These cells differentiate first into mitotically active cells, myoblasts, which contain a few myofilaments. Myoblasts give rise to the cells which will differentiate into mature smooth muscle cells.

* Skeletal muscle - cells originate from the paraxial mesoderm. Myoblasts undergo frequent divisions and coalesce with the formation of a multinucleated, syncytial muscle fibre or myotube. The nuclei of the myotube are still located centrally in the muscle fibre. In the course of the synthesis of the myofilaments/myofibrils, the nuclei are gradually displaced to the periphery of the cell.

* Cardiac muscle - cells originate from the prechordal splanchnic mesoderm.

===Skeletal Muscle Stages===

'''Myoblast''' - individual progenitor cells

'''Myotube''' - multinucleated, but undifferentiated contractile apparatus (sarcomere)

'''Myofibre''' (myofiber, muscle cell) - multinucleated and differentiated sarcomeres
* primary myofibres - first-formed myofibres, act as a structural framework upon which myoblasts proliferate, fuse in linear sequence
* secondary myofibers - second later population of myofibres that form surrounding the primary fibres.

'''Muscle Fibre Types'''
* type IIB, IIA, IIX, and I fibres - based only on the myosin ATPase activity.
** Type I fibres appear red, due to the presence of myoglobin
** Type II fibres appear white, due to the absence of myoglobin and their glycolytic nature.
* A group of individual myofibres within a muscle will be innervated by a single motor neuron.
* The electrical properties of the motor neuron will regulate the contractile properties of all associated myofibres.

'''MH-''' you do not need to know the table below in detail, it is provided for information purposes only.

{|class="wikitable"
|-
!bgcolor="LightSteelBlue"|Fibre Type ||bgcolor="LightSteelBlue"|Type I fibres ||bgcolor="LightSteelBlue"|Type II a fibres ||bgcolor="LightSteelBlue"|Type II x fibres ||bgcolor="LightSteelBlue"|Type II b fibres
|-
|Contraction time ||Slow ||Moderately Fast ||Fast ||Very fast
|-
|Size of motor neuron ||Small ||Medium ||Large ||Very large
|-
|Resistance to fatigue ||High || Fairly high ||Intermediate ||Low
|-
|Activity Used for ||Aerobic ||Long-term anaerobic ||Short-term anaerobic ||Short-term anaerobic
|-
|Maximum duration of use ||Hours||<30 minutes||<5 minutes||<1 minute
|-
|Power produced ||Low ||Medium ||High ||Very high
|-
|Mitochondrial density ||High ||High ||Medium ||Low
|-
|Capillary density ||High ||Intermediate ||Low ||Low
|-
|Oxidative capacity ||High ||High ||Intermediate ||Low
|-
|Glycolytic capacity ||Low ||High ||High ||High
|-
|Major storage fuel ||Triglycerides ||Creatine phosphate, glycogen ||Creatine phosphate, glycogen ||Creatine phosphate, glycogen
|-
|Myosin heavy chain, human genes || MYH7 || MYH2 ||MYH1 || MYH4
|}

===Myotome===

This term is used to describe the region of the somite that contributes skeletal muscle to the embryo body. Each somite pair level gives rise to a group of skeletal muscles supplied by a specific segmental spinal nerve. The muscle arises from a specific somite and the spinal nerve arises from a specific level of the spinal cord (identified by vertebral column).

In humans this corresponds to the following spinal nerves (from top to bottom) and muscular functions:
* C3,4 and 5 supply the diaphragm for breathing.
* C5 supply shoulder muscles and muscles to bend our elbow.
* C6 for bending the wrist back.
* C7 for straightening the elbow.
* C8 bends the fingers.
* T1 spreads the fingers.
* T1 –T12 supplies the chest wall and abdominal muscles.
* L2 bends the hip.
* L3 straightens the knee.
* L4 pulls the foot up.
* L5 wiggles the toes.
* S1 pulls the foot down.
* S3,4 and 5 supply the bladder, bowel, sex organs, anal and other pelvic muscles.

==Puberty==
* Musculoskeletal mass doubles by the end of puberty
* regulated growth by - sex steroid hormones, growth hormone, insulin-like growth factors
* accumulation of (peak) bone mass during puberty relates to future osteoporosis in old age

==Abnormalities==
Additional abnormalities will be covered in the limb development lecture. [http://embryology.med.unsw.edu.au/Notes/skmus2.htm see also Musculoskeletal Abnormalities]
[[File:Australian abnormalities graph allsystem.png|300px]][[File:Australian abnormalities pie skmus.png|300px]]
===Bone===
====Vertebra====
* Spina Bifida - neural tube failure to close, disrupts neural arch formation
* Block vertebra - failure of vertebra separation, lumbar region, chrondrification abnormality
* Klippel-Feil Syndrome - non-segmented cervical vertebra, more female
* see also [[#scoliosis|scoliosis]]

====Rib====
* Accessory rib (extra rib cervical or lumbar uni- or bilateral), short-rib polydactyly syndrome (lethal, chondroplasia), pigeon chest (rib overgrowth), funnel chest (sternum depression and lower costal cartilages)

====Osteogenesis Imperfecta====
* brittle-bone syndrome
* abnormal collagen type I, fail to assemble triple helix, degrade imperfect collagen, leads to fragile bones

====Scoliosis====
[[File:Scoliosis.jpg]][[File:Scoliosis xray.jpg]]
* assymetric growth impairment of vertebral bodies
* lateral deviation of spine (Lateral flexion, Forward flexion, Rotation of vertebral column on long axis)
* compensated by movement of vertebral column above and below affected region (producing a primary and two secondary curves)
* progresses rapidly in adolescence and becomes fixed once bone growth is completed.

====Congenital Hip Dislocation====
[[File:Congenital dislocation hip.jpg|thumb|Congenital Hip Dislocation]]
* Instability: 1:60 at birth; 1:240 at 1 wk: Dislocation untreated; 1:700
* congenital instability of hip, later dislocates by muscle pulls or gravity
* familial predisposition female predominance
* Growth of femoral head, acetabulum and innominate bone are delayed until the femoral head fits firmly into the acetabulum

===Muscle===

'''MH''' - Covered in next lecture and lab.
====Congenital Myopathies====

====Muscular Dystrophy====
[http://embryology.med.unsw.edu.au/Notes/skmus2.htm#Muscular%20Dystrophy Muscular Dystrophy]

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter Chapter 10 The Pharyngeal Apparatus pp201 - 240.
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 12 Development of the Head, the Neck, the Eyes, and the Ears pp349 - 418.

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.chapter.3450 Paraxial and intermediate mesoderm] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3475 Myogenesis: The Development of Muscle] | [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=dbio.section.3479 Osteogenesis: The Development of Bones] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.figgrp.3478 Figure 14.10. Conversion of myoblasts into muscles in culture]

* '''Molecular Biology of the Cell''' Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=mboc4.TOC&depth=2 Search Molecular Biology of the Cell][http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.section.4177#4187 Bone Is Continually Remodeled by the Cells Within It][http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.figgrp.4191 Image: Figure 22-52. Deposition of bone matrix by osteoblasts.][http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.figgrp.4196 Image: Figure 22-56. The development of a long bone.]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=mesoderm mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=somite somite] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=myogenesis myogenesis] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=chondrogenesis chondrogenesis] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=osteogenesis osteogenesis]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=mesoderm mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=somite somite] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=myogenesis myogenesis] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=chondrogenesis chondrogenesis] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=osteogenesis osteogenesis]

== UNSW Embryology Links ==
* '''Notes:''' [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Bone Development] | [http://embryology.med.unsw.edu.au/Notes/skmus7.htm Limb Development] | [http://embryology.med.unsw.edu.au/Notes/skmus8.htm Axial Skeleton Development] | [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Bone Development] | [http://embryology.med.unsw.edu.au/Notes/skmus8a.htm Skull | Development] [http://embryology.med.unsw.edu.au/Notes/skmus7.htm Limb] | [http://embryology.med.unsw.edu.au/Notes/skmus8.htm Axial Skeleton]| [http://embryology.med.unsw.edu.au/Notes/skmus9a.htm Human Bone] | [http://embryology.med.unsw.edu.au/Notes/skmus9b.htm Endochondral Ossification] | [http://embryology.med.unsw.edu.au/Notes/skmus12.htm Skeletal Muscle] | [http://embryology.med.unsw.edu.au/Notes/skmus30.htm Cartilage] | [http://embryology.med.unsw.edu.au/Notes/skmus31.htm Joints]

* '''Lectures:''' [http://embryology.med.unsw.edu.au/Science/ANAT2341lecture16.htm ANAT2341 - Embryology 2008 - Lecture 16]
* '''Movies:''' [http://embryology.med.unsw.edu.au/Movies/mesoderm.htm Mesoderm Movies] | [http://embryology.med.unsw.edu.au/Movies/mesoderm/somite2.mov Somite - Myotome body wall] | [http://embryology.med.unsw.edu.au/Movies/mesoderm/vertabra3.mov Vertebra]

== External Links ==

* '''UWA Blue Histology''' [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Muscle/Muscle.htm Skeletal Tissues - Muscle] | [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Cartilage/Cartil.htm Skeletal Tissues -Cartilage] | [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Bone/Bone.htm Skeletal Tissues - Bone]

* '''University of Kansas Histoweb''' [http://www.kumc.edu/instruction/medicine/anatomy/histoweb/bone/bone.htm Bone]

* '''Loyola University Medical Education Network''' [http://www.lumen.luc.edu/lumen/MedEd/Histo/frames/h_frame9.html Part 9: Specialized Connective Tissue: Cartilage and Bone] | [http://www.lumen.luc.edu/lumen/MedEd/Histo/frames/h_frame10.html Part 10: Endochondral Ossification]

* '''UNSW Embryology''' [http://embryology.med.unsw.edu.au/histology/cartilagebone/cartbone1.html Cartilage and Bone]

* '''University of Bristol''' [http://www.e-radiography.net/articles/ossification/ossification.htm ossification]

== Terms ==
'''annulus fibrosus -''' the circularly arranged fibers (derived from sclerotome)that together with the nucleus pulposus (derived from notochord) form the [[#intervertebral disc|intervertebral disc]] (IVD) of the vertebral column.

'''axial mesoderm -''' (=notochord)

'''cartilage -''' connective tissue from mesoderm in the embryo forms the initial skeleton which is replaced by bone. In adult, found on surface of bone joints.

'''Cbfa1''' - Core-Binding Factor 1 (Runx2) transcription factor protein key to the differentiation of bone [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600211 OMIM: Cbfa1]

'''centrum -''' the primordium of the [[#vertebral body|vertebral body]] formed initially by the sclerotome.

'''clavicle -''' (Latin, ''clavicle'' = little key) bone which locks shoulder to body.

'''dermatome -'''

'''dermomyotome''' - dorsolateral half of each somite that forms the dermis and muscle.

'''ectoderm -''' the layer (of the 3 germ cell layers) which form the nervous system from the neural tube and neural crest and also generates the epithelia covering the embryo.

'''endochondrial ossification -''' the process of replacement of the cartilagenous framework by osteoblasts with bone.

'''epaxial myotome -''' the dorsal portion of the myotome that generates dorsal skeletal muscles (epaxial muscles), which include other muscles associated with the vertebrae, ribs, and base of the skull.

'''extracellular matrix -''' material secreted by and surrounding cells. Consists if fibers and ground substance.

'''fibroblast growth factors -''' (FGF) a family of at least 10 secreted proteins that bind membrane tyrosine kinase receptors. A patterning switch with many different roles in different tissues. (FGF8 = androgen-induced growth factor (AIGF)

'''fibroblast growth factor receptor - '''receptors comprise a family of at least 4 related but individually distinct tyrosine kinase receptors (FGFR1- 4). They have a similar protein structure, with 3 immunoglobulin-like domains in the extracellular region, a single membrane spanning segment, and a cytoplasmic tyrosine kinase domain.

'''growth factor -''' usually a protein or peptide that will bind a cell membrane receptor and then activates an intracellular signaling pathway. The function of the pathway will be to alter the cell directly or indirectly by changing gene expression. (eg shh)

'''hox -''' (='''h'''omeob'''ox''') family of transcription factors that bind DNA and activate gene expression. Expression of different Hox genes along neural tube defines rostral-caudal axis and segmental levels.

'''hypaxial myotome -''' the ventral portion of the myotome that generates ventral skeletal muscles (hypaxial muscles) which include some vertebral muscles, the diaphragm, the abdominal muscles, and all limb muscles.

'''intercostal-''' the region between adjacent ribs, usually comprising intercostal muscles and connective tissue.

'''intervertebral disc-''' (IVD) the annulus fibrosus+nucleus pulposus together form the intervertebral disc (IVD) of the vertebral column. This is the flexible region between each bony vertebra that allows the column to be bent.

'''lumbar plexus -''' mixed spinal nerves innervating the lower limb form a complex meshwork (crossing).

'''mesenchymal progenitor cells - ''' (MPCs) cells able to differentiate in various types of connective tissue, including cartilage, bone and adipose tissue.

'''mesoderm -''' the middle layer of the 3 germ cell layers of the embryo. Mesoderm outside the embryo and covering the amnion, yolk and chorion sacs is extraembryonic mesoderm.

'''myoblast -''' the undifferentiated mononucleated muscle cells that will fuse together to form a multinucleated myotube, then mature into a muscle fibre.

'''MyoD -''' transcription factor involved in the determination of muscle cells in the somite. A basic helix-loop-helix factor which binds DNA.

'''myotome -''' the portion of the dermamyotome that generates skeletal muscle. Has 2 components epaxial (dorsal muscles ) hypaxial (ventral muscles).

'''neural crest -''' cell region at edge of neural plate, then atop the neural folds, that remains outside and initially dorsal to the neural tube when it forms. These paired dorsal lateral streaks of cells migrate throughout the embryo and can differentiate into many different cell types(=pluripotential). Those that remain on the dorsal neural tube form the sensory spinal ganglia (DRG). Neural crest cells migrate into the somites.

'''osteoblast''' - The mesenchymal cells that differentiate to form the cellular component of bone and produce bone matrix. Mature osteoblasts are called osteocytes. (More? [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Musculoskeletal Development - Bone])

'''osteoclast''' - Cells that remove bone (bone resorption) by enzymatically eroding the bone matrix. These cells are monocyte-macrophage in origin and fuse to form a multinucleated osteoclast. These cells allow continuous bone remodelling and are also involved in calcium and phosphate metabolism. The erosion cavity that the cells lie iwithin and form is called Howship's lacuna. (More? [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Musculoskeletal Development - Bone])

'''osteocyte''' - The mature bone-forming cell, which form the cellular component of bone and produce bone matrix. Differentiate from osteoblasts, mesenchymal cells that differentiate to form bone. (More? [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Musculoskeletal Development - Bone])

'''osteon''' - The anatomical (histological) unit structure (principal structure) of compact bone. (More? [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Musculoskeletal Development - Bone])

'''Pax -''' name derived from Drosophila gene 'paired' (prd) the 'paired box' is a amino end 124 amino-acid conserved domain (signature aa 35-51: '''P-C-x(11)-C-V-S'''). Transcription factor of the helix-turn-helix structural family, DNA binding, and activating gene expression. In human, nine member proteins from Pax-1 to Pax-9. Regulate differentiation of many different tissues. Some members of the family (PAX3, PAX4, PAX6, PAX7) also contain a functional homeobox domain.

'''pedicle -''' (Latin, ''pediculus'' = small foot) part of the vertebral arch forming the segment between the transverse process and the vertebral body.

'''primary centre of ossification -''' the first area where bone growth occurs between the periosteum and cartilage.

'''sclerotome -''' ventromedial half of each somite that forms the vertebral body and intervertebral disc.

'''segmentation -''' to break a solid structure into a number of usually equal size pieces.

'''somatic mesoderm -''' derived from lateral mesoderm closest to the ectoderm and separated from other component of lateral mesoderm (splanchnic, near endoderm) by the intraembryonic coelom.

'''somite -''' segmental block (ball) of mesoderm formed from paraxial mesoderm adjacent to notochord (axial mesoderm). Differentiates to form initially sclerotome and dermamyotome (then dermotome and myotome).

'''somitic mesoderm-'''

'''somitocoel -''' a transient cavity that appears within each of the the early forming somites then is lost.

'''somitogenesis -''' the process of segmentation of the paraxial mesoderm to form "mesoderm balls" beginning cranially (humans day20) and extending caudally at 1 somite/90 minutes until approx. 44 pairs have been formed.

'''sonic hedgehog -''' (=shh) secreted growth factor that binds patched (ptc) receptor on cell membrane. SHH function is different for different tissues in the embryo. In the nervous system, it is secreted by the notochord, ventralizes the neural tube, inducing the floor plate and motor neurons. In the Limb it is secreted by the zone of polarizing activity (ZPA) organizing limb axis formation.

'''Tbx -''' T-box genes (transcription factor) involved in mouse forelimb (Tbx4) and hindlimb (Tbx5) specification.

'''transcription factor-''' a factor (protein or protein with steroid) that binds to DNA to alter gene expression, usually to activate. (eg steroid hormone+receptor, Retinoic acid+Receptor, Hox, Pax, Lim, Nkx-2.2).

'''vertebral body-''' formed by centrum, vertebral arch, facets for ribs. It is the mature vertebral structure formed by the 5 secondary ossification centers after puberty.

'''vertebral column -''' name given to the complete structure formed from the alternating segments of vertebra and intervertebral discs which support the spinal cord.

'''vertebral foramen -''' the dorsal cavity within each vertebra, generated by the vertebral arch that surrounds the spinal cord.

'''Wnt7a -''' The designation 'Wnt' was derived from 'wingless' and 'int'. The Wnt gene was first defined as a protooncogene, int1. Humans have at least 4 Wnt genes: Wnt7a gene is at 3p25 encoding a 349aa secreted glycoprotein. A patterning switch with different roles in different tissues. The mechanism of Wnt distribution (free diffusion, restricted diffusion and active transport) and all its possible cell receptors are still being determined. At least one WNT receptor is Frizzled (FZD). The Frizzled gene family encodes a seven-transmembrane receptor.

==Images==
<gallery>
File:Bone remodeling cycle.jpg|Bone remodeling cycle
</gallery>

{{Glossary}}
{{Footer}}

File:Musculoskeletal.pdf

2013-09-16T07:18:48Z

Z3283213:

File:Limb development.pdf

2013-09-16T07:18:19Z

Z3283213:

Lecture - Limb Development

2013-09-11T05:21:48Z

Z3283213:

==Introduction==
[[File:Appendicular skeleton.jpg|thumb|400px]]
This lecture is an introduction to the events in limb development. Cells of the ectoderm, cells derived from the dermatome and the hypaxial portion of the myotome mix with somatic component of the lateral plate mesoderm to give rise to the fore and hind limbs.

The appendicular skeleton consists of: Shoulder girdle, Upper limb (arm, hand), Pelvic girdle, Lower limb (leg, foot).

[[:File:Human_Carnegie_stage_1-23.jpg|Carnegie stage 1-23]]

==Lecture Objectives==
[[File:Stage14 sem2b-limb.jpg|thumb|Human Embryo stage 14 SEM]]

* Understanding of limb positioning
* Understanding of differences in developmental timing of upper and lower limbs
* Understanding of limb patterning - regions and factors determining the limb axes
* Understanding of limb rotation
* Understanding of limb muscle, blood vessel, bone and nerve formation
* Brief understanding of limb molecular factors and cell death
* Brief understanding of limb abnormalities

==Information==

Lecture Date: 2013-09-17 Lecture Time: 16:00 Venue: BioMed E Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document

The audio will be available via the Lectopia system through Blackboard

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (chapter links only work with a UNSW connection).
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00016-3&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00016-3 Chapter 16 – Development of Limbs]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (chapter links only work with a UNSW connection).

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10018-1 Chapter 18 - Development of the Limbs]
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

* [[Musculoskeletal System - Limb Development|Limb Development]]
* [[Musculoskeletal System - Limb Abnormalities|Limb Abnormalities]]
* '''Developmental Dynamics''' - Special Issue: [http://onlinelibrary.wiley.com/doi/10.1002/dvdy.v240.5/issuetoc Special Issue on Limb Development] May 2011 Volume 240, Issue 5
|}

:'''Links:''' [[Embryology_Textbooks_-_UNSW|UNSW Textbooks]] | [[Embryology Textbooks]]

==Limb Buds==
* Limbs are initially undifferentiated mesenchyme (mesoderm) with an epithelial (ectoderm) covering. Uniform paddle shaped structures that grow outwards gradually.
* One the first noticeable changes is the development of a large blood vessel (marginal vein) which runs just underneath a thickening of the ectoderm at the tip of the limb bud called the Apical Ectodermal Ridge (AER).
* Positioning of the limbs is distant from final location

==Upper and Lower Limb==
[[File:Stage20-23 limbs a.jpg]]
[[File:Stage14_somites_limbbuds.png|thumb]]
Limb development occurs at different times for forelimbs and hindlimbs. In the mid-4th week, human upper limb buds first form and lower limbs about 2 days later. The limbs form at vertebra segmental levels C5-C8 (upper limbs) L3-L5 (lower limbs).

==Limb Axis Formation==

Four Concepts - much of the work has been carried out using the chicken and more recently the mouse model of development.

# Limb Initiation
# Proximodistal Axis
# Dorsoventral Axis
# Anteroposterior Axis

===Limb Initiation===
* Fibroblast growth factor (FGF) coated beads can induce additional limb
* FGF10 is expressed in lateral plate mesoderm prior to bud formation induces expression of FGF8 in the overlying ectoderm. FGF8 induces continued growth in the underlying mesoderm - thus a positive feedback loop
* Anterior boundary of Hoxc6 expression coincides with the position of forelimb development

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3941&rendertype=figure&id=A3953 Autoregulatory loop of induction between FGF10 and FGF8]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A1038&rendertype=figure&id=A1041 Site of FGF10 expression in the chick embryo]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3881 Positioning of the limb on the rostrocaudal (anteroposterior) axis is determined by the expression of Hox genes]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3882 Examples of Hox gene expression boundaries in the mouse Hoxb2 and Hoxb4]

===Limb Identity===

Forelimb and hindlimb (mouse) identity appears to be regulated by T-box (Tbx) genes, which are a family of transcription factors.
* hindlimb Tbx4 is expressed.
* forelimb Tbx5 is expressed.
* Tbx2 and Tbx3 are expressed in both limbs.

'''Related Research''' - [http://www.ncbi.nlm.nih.gov/pubmed/12490567?dopt=Abstract PMID: 12490567] | [http://dev.biologists.org/cgi/content/figsonly/130/3/623 Development 2003 Figures] | [http://dev.biologists.org/cgi/content/full/130/3/623/FIG1 Scanning electron micrographs of E9 Limb bud wild-type and Tbx5del/del] [http://dev.biologists.org/cgi/content/full/130/3/623/FIG7 A model for early stages of limb bud growth] | [http://www.ncbi.nlm.nih.gov/pubmed/12736217?dopt=Abstract PMID: 12736217] | [http://dev.biologists.org/cgi/content/figsonly/130/12/2741 Development 2003 Figures]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3928&rendertype=figure&id=A3936 Tbx4 expression can turn an experimentally induced forelimb into a hindlimb]

==Axes and Morphogens==
[[File:Limb bud geometry and patterning.jpg|thumb|Limb bud geometry and patterning]]
* '''Anteroposterior''' - (Rostrocaudal, Craniocaudal, Cephalocaudal) from the head end to opposite end of body or tail.
* '''Dorsoventral''' - from the spinal column (back) to belly (front).
* '''Proximodistal''' - from the tip of an appendage (distal) to where it joins the body (proximal).

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3885&rendertype=figure&id=A3902 Model of patterning signals in the vertebrate limb]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3792&rendertype=figure&id=A3812 Diffusible morphogens create a concentration gradient accross an embryonic field]

===Proximodistal Axis===
* Apical Ectodermal Ridge (AER) initially formed at the site of FGF10 induction
* then AER secretes FGF8 and FGF4 slightly later
* FGFs stimulate proliferation and outgrowth in the underlying mesenchyme

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb017.htm limb development at embryo images online]

=====Morphogen production from the AER - The Fibroblast Growth Factors (FGFs)=====
* 22 FGF genes identified in humans
* bind membrane tyrosine kinase receptors
* Patterning switch with many different roles in different tissues

FGF receptors
* comprise a family of at least 4 related but individually distinct tyrosine kinase receptors (FGFR1- 4) similar protein structure
* 3 immunoglobulin-like domains in extracellular region
* single membrane spanning segment
* cytoplasmic tyrosine kinase domain

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A1038&rendertype=figure&id=A1041 FGF receptors are paired proteins on the cell surface with an internal tyrosine kinase domain]

===Dorsoventral Axis===
* Important for patterning muscles - ventral muscles - flexors; Dorsal muscles - extensors
* Early grafting experiments showed that the D/V signalling centre resided in the dorsal ectoderm
* Wnt7a is a diffusible morphogen that is secreted by dorsal ectoderm cells
* Wnt7a induces the expression of the homeobox gene Lmx1 in the underlying mesoderm adjacent to the dorsal surface
* The homeobox gene Engrailed (En1) is expressed in the opposite ventral ectoderm

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3968&rendertype=figure&id=A3969 Consequence of Wnt7a deficiency in the mouse forelimb]

===== Morphogen production from the dorsal ectoderm - Wnt7a=====
* name was derived from 'wingless' and 'int’
* Wnt gene first defined as a protooncogene, int1
* Humans have 19 Wnt genes
* Wnt7a gene is at 3p25 encoding a 349aa secreted glycoprotein
* patterning switch with different roles in different tissues
* One WNT receptor is called Frizzled (FZD) - named after a drosophila phenotype
* Frizzled gene family encodes a G protein-coupled receptor with 7 transmembrane domains

===Anteroposterior Axis===
* Zone of polarizing activity (ZPA)
* a mesenchymal posterior region of limb
* secretes sonic hedgehog (SHH)

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3792&rendertype=figure&id=A3815 ZPA secretes SHH and determines the anteroposterior axis of the limb bud]

=====Morphogen production from the ZPA - Sonic Hedgehog (SHH)=====

* Sonic hedgehog (SHH) is a diffusible morphogen secreted from cells, the protein product of the SHH gene
* The protein is processed by cleavage of the preprotein and addition of a palmitate molecule to the amino terminus and cholesterol to the carboxy terminus
* The SHH receptor is a cell surface protein called Patched which interacts with another cell surface protein Smoothened.
* Binding of SHH to Patched blocks its inhibitory effect on Smoothened and allows it to initiate an intracellular signaling cascade

===The Time Axis - Dynamic development and temporal gene expression===

* Different Hox genes are expressed at different times in the developing limb bud and pattern the fine structure of the limb.
* Structures are determined in a proximal>distal direction with time, i.e. proximal structures such as the humerus bone are laid down first.

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3941&rendertype=figure&id=A3956 Hox genes and dynamic patterning of the limb]

==Cellular origins of the limb==

===Limb cartilage and bone===
* Derived from local proliferating mesenchyme derived from the somatic lateral plate mesoderm (somatopleure)
* BMP2 and BMP4 play crucial roles in the development of cartilage - sufficient BMP must be present to achieve chondrogenesis. However, the main role is in later bone formation. Loss of BMP2 and 4 leads to a severe impairment of osteogenesis

[[Image:Mesoderm cartoon4.gif]]

[http://www.ncbi.nlm.nih.gov/books/NBK10085/figure/A3468/?report=objectonly - Differentiation of somitic mesoderm in the chick embryo]

===Limb muscle and dermis===
* Skeletal muscle derived from somites, the hypaxial part of the myotome
* Pax3 positive migratory myoblasts invade the limb bud
* Similarly, dermal cells also invade derived from the dermomyotome
* Both maintain the identity of the somite from which they were derived so that innervation corresponds to the same spinal nerve root.
* Note that dermatomes are rotated due to embryonic limb rotations

Origin of limb muscle cells - Migrations traced by grafting cells from a quail embryo into a chick embryo
* two species very similar in development
* quail cells recognizable by distinctive nucleoli
* Quail somite cells substituted for somite cells of 2 day chick embryo
* wing of chick sectioned a week later
* found muscle cells in chick wing derive from transplanted quail somites

Dorsal/Ventral Muscle Mass - sometimes referred to as the anterior and posterior muscle compartments. The posterior compartment of the lower hindlimb is mainly made up of the gastrocnemius muscles, the plantaris muscle and the soleus muscle.

Forelimb Muscles

Limb Muscle - Differentiation of Skeletal muscle is the same as in the myotome blocks but involves an extra migratory step

# Muscle precursor cells migrate to the muscle location
# Form beds of proliferating myoblasts
# Myoblasts fuse together to form a syncitial structure called a myotube
# Myotubes begin to express contractile proteins, form sarcomeres
# mature into myofibers with tendon connections at each end, motor and sensory innervation.

==Hand and Footplates==
[[File:BMP syndactyly.jpg|thumb|Depletion of BMP Signaling Causes Interdigital Syndactyly]]
* 5th week- hand and footplates appear at the ends of limb buds and ridges form digital rays
* Cells between the digital rays are removed by programmed cell death (apoptosis)
* 3-5 day difference between hand and foot development

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb024.htm hand growth]

===Apoptosis===

[http://php.med.unsw.edu.au/cellbiology/index.php?title=2009_Lecture_18 Cell Biology - Apoptosis Lecture]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3245&rendertype=figure&id=A3246 Fluorescent staining of cells undergoing apoptosis in the limb]

==Limb Rotation==
[[File:Stage20-23 limbs a.jpg|thumb]]
* 8th week limbs rotate in different directions (Humans Stage 20-23)
* thumb and toe rostral
* knee and elbow face outward
* '''upper limb rotates dorsally'''
* '''lower limb rotates ventrally'''

==Limb Innervation==
[[File:Gray0807.gif|thumb|brachial plexus]]
[[File:Dermatomes.png|thumb|Adult Dermatomes]]
* spinal cord segmental nerves form a plexus adjacent to each limb
* Brachial (upper) lumbar (lower)
* Plexus forms as nerves invade the limb bud mesechyme
* Fetal period - touch pads become visible on hands and feet

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb019.htm brachial plexus origin]

==Limb Abnormalities==

===Congenital Hip Dislocation===
[[File:Congenital dislocation hip.jpg|thumb|Congenital Hip Dislocation]]
* Instability of the femoral head in the acetabulum - ligaments may stretch: 1:60 at birth
* congenital instability of hip, later dislocates by muscle pulls or gravity
* familial predisposition female predominance
* Growth of femoral head, acetabulum and innominate bone are delayed until the femoral head fits firmly into the acetabulum

[http://embryology.med.unsw.edu.au/Notes/skmus72.htm limb abnormalities]

===Maternal===
* thalidomide Phocomelia
* short ill-formed upper or lower limbs
* hyperthermia

===Genetic===
* Trisomy 21 - Downs syndrome [[File:Trisomy21_hand.jpg|thumb]]
* Human Gene Mutations - mutation of any of the patterning genes will result in limb abnormalities
Type II syndactyly- HoxD13

===Muscle Development===
Duchenne Muscular Dystrophy
* X-linked dystrophy
* large gene encoding cytoskeletal protein- Dystrophin
* progressive wasting of muscle, die late teens

Becker Muscular Dystrophy
* milder form, adult onset

==Online Links==
* UNSW Embryology [http://embryology.med.unsw.edu.au/Notes/skmus7.htm Limb Development]
* Embryo Images [http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimbtoc.htm Limb Unit]
* International J. Dev. Biology Vol 46 [http://www.ijdb.ehu.es/0207contents.htm Special Issue- Limb Development 2002]
* Research Labs - [http://pages.unibas.ch/anatomie/zeller/seiten/seite1.html Rolf Zeller University of Basel Medical School]

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West -

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3928 Formation of the Limb Bud] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3941 Generating the Proximal-Distal Axis of the Limb]

* '''Molecular Biology of the Cell''' Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=limb_development&rid=mboc4.figgrp.3815 Figure 21-13. Sonic hedgehog as a morphogen in chick limb development]

* '''Madame Curie Bioscience Database''' Chapters taken from the Madame Curie Bioscience Database (formerly, Eurekah Bioscience Database)

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=limb_development limb development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=limb_development limb development]

==Images==
===Stage13===
[[File:Stage13 bf1c.jpg]] [[File:Stage13 sem1c.jpg]]
===Stage14===
[[File:Stage14_bf2cl.jpg]] [[File:Stage14_sem1c.jpg]]

{{Glossary}}
{{Footer}}

Lecture - Limb Development

2013-09-11T05:21:21Z

Z3283213:

<div style="background:#F5FFFA; border: 1px solid #CEF2E0; padding: 1em; margin: auto; width: 95%; float:left;"><div style="margin:0;background-color:#cef2e0;font-family:sans-serif;font-size:120%;font-weight:bold;border:1px solid #a3bfb1;text-align:left;color:#000;padding-left:0.4em;padding-top:0.2em;padding-bottom:0.2em;"> Lecturer : Dr Steve Palmer</div></div>

==Introduction==
[[File:Appendicular skeleton.jpg|thumb|400px]]
This lecture is an introduction to the events in limb development. Cells of the ectoderm, cells derived from the dermatome and the hypaxial portion of the myotome mix with somatic component of the lateral plate mesoderm to give rise to the fore and hind limbs.

The appendicular skeleton consists of: Shoulder girdle, Upper limb (arm, hand), Pelvic girdle, Lower limb (leg, foot).

[[:File:Human_Carnegie_stage_1-23.jpg|Carnegie stage 1-23]]

==Lecture Objectives==
[[File:Stage14 sem2b-limb.jpg|thumb|Human Embryo stage 14 SEM]]

* Understanding of limb positioning
* Understanding of differences in developmental timing of upper and lower limbs
* Understanding of limb patterning - regions and factors determining the limb axes
* Understanding of limb rotation
* Understanding of limb muscle, blood vessel, bone and nerve formation
* Brief understanding of limb molecular factors and cell death
* Brief understanding of limb abnormalities

==Information==

Lecture Date: 2013-09-17 Lecture Time: 16:00 Venue: BioMed E Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document

The audio will be available via the Lectopia system through Blackboard

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (chapter links only work with a UNSW connection).
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00016-3&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00016-3 Chapter 16 – Development of Limbs]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (chapter links only work with a UNSW connection).

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10018-1 Chapter 18 - Development of the Limbs]
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

* [[Musculoskeletal System - Limb Development|Limb Development]]
* [[Musculoskeletal System - Limb Abnormalities|Limb Abnormalities]]
* '''Developmental Dynamics''' - Special Issue: [http://onlinelibrary.wiley.com/doi/10.1002/dvdy.v240.5/issuetoc Special Issue on Limb Development] May 2011 Volume 240, Issue 5
|}

:'''Links:''' [[Embryology_Textbooks_-_UNSW|UNSW Textbooks]] | [[Embryology Textbooks]]

==Limb Buds==
* Limbs are initially undifferentiated mesenchyme (mesoderm) with an epithelial (ectoderm) covering. Uniform paddle shaped structures that grow outwards gradually.
* One the first noticeable changes is the development of a large blood vessel (marginal vein) which runs just underneath a thickening of the ectoderm at the tip of the limb bud called the Apical Ectodermal Ridge (AER).
* Positioning of the limbs is distant from final location

==Upper and Lower Limb==
[[File:Stage20-23 limbs a.jpg]]
[[File:Stage14_somites_limbbuds.png|thumb]]
Limb development occurs at different times for forelimbs and hindlimbs. In the mid-4th week, human upper limb buds first form and lower limbs about 2 days later. The limbs form at vertebra segmental levels C5-C8 (upper limbs) L3-L5 (lower limbs).

==Limb Axis Formation==

Four Concepts - much of the work has been carried out using the chicken and more recently the mouse model of development.

# Limb Initiation
# Proximodistal Axis
# Dorsoventral Axis
# Anteroposterior Axis

===Limb Initiation===
* Fibroblast growth factor (FGF) coated beads can induce additional limb
* FGF10 is expressed in lateral plate mesoderm prior to bud formation induces expression of FGF8 in the overlying ectoderm. FGF8 induces continued growth in the underlying mesoderm - thus a positive feedback loop
* Anterior boundary of Hoxc6 expression coincides with the position of forelimb development

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3941&rendertype=figure&id=A3953 Autoregulatory loop of induction between FGF10 and FGF8]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A1038&rendertype=figure&id=A1041 Site of FGF10 expression in the chick embryo]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3881 Positioning of the limb on the rostrocaudal (anteroposterior) axis is determined by the expression of Hox genes]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3882 Examples of Hox gene expression boundaries in the mouse Hoxb2 and Hoxb4]

===Limb Identity===

Forelimb and hindlimb (mouse) identity appears to be regulated by T-box (Tbx) genes, which are a family of transcription factors.
* hindlimb Tbx4 is expressed.
* forelimb Tbx5 is expressed.
* Tbx2 and Tbx3 are expressed in both limbs.

'''Related Research''' - [http://www.ncbi.nlm.nih.gov/pubmed/12490567?dopt=Abstract PMID: 12490567] | [http://dev.biologists.org/cgi/content/figsonly/130/3/623 Development 2003 Figures] | [http://dev.biologists.org/cgi/content/full/130/3/623/FIG1 Scanning electron micrographs of E9 Limb bud wild-type and Tbx5del/del] [http://dev.biologists.org/cgi/content/full/130/3/623/FIG7 A model for early stages of limb bud growth] | [http://www.ncbi.nlm.nih.gov/pubmed/12736217?dopt=Abstract PMID: 12736217] | [http://dev.biologists.org/cgi/content/figsonly/130/12/2741 Development 2003 Figures]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3928&rendertype=figure&id=A3936 Tbx4 expression can turn an experimentally induced forelimb into a hindlimb]

==Axes and Morphogens==
[[File:Limb bud geometry and patterning.jpg|thumb|Limb bud geometry and patterning]]
* '''Anteroposterior''' - (Rostrocaudal, Craniocaudal, Cephalocaudal) from the head end to opposite end of body or tail.
* '''Dorsoventral''' - from the spinal column (back) to belly (front).
* '''Proximodistal''' - from the tip of an appendage (distal) to where it joins the body (proximal).

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3885&rendertype=figure&id=A3902 Model of patterning signals in the vertebrate limb]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3792&rendertype=figure&id=A3812 Diffusible morphogens create a concentration gradient accross an embryonic field]

===Proximodistal Axis===
* Apical Ectodermal Ridge (AER) initially formed at the site of FGF10 induction
* then AER secretes FGF8 and FGF4 slightly later
* FGFs stimulate proliferation and outgrowth in the underlying mesenchyme

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb017.htm limb development at embryo images online]

=====Morphogen production from the AER - The Fibroblast Growth Factors (FGFs)=====
* 22 FGF genes identified in humans
* bind membrane tyrosine kinase receptors
* Patterning switch with many different roles in different tissues

FGF receptors
* comprise a family of at least 4 related but individually distinct tyrosine kinase receptors (FGFR1- 4) similar protein structure
* 3 immunoglobulin-like domains in extracellular region
* single membrane spanning segment
* cytoplasmic tyrosine kinase domain

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A1038&rendertype=figure&id=A1041 FGF receptors are paired proteins on the cell surface with an internal tyrosine kinase domain]

===Dorsoventral Axis===
* Important for patterning muscles - ventral muscles - flexors; Dorsal muscles - extensors
* Early grafting experiments showed that the D/V signalling centre resided in the dorsal ectoderm
* Wnt7a is a diffusible morphogen that is secreted by dorsal ectoderm cells
* Wnt7a induces the expression of the homeobox gene Lmx1 in the underlying mesoderm adjacent to the dorsal surface
* The homeobox gene Engrailed (En1) is expressed in the opposite ventral ectoderm

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3968&rendertype=figure&id=A3969 Consequence of Wnt7a deficiency in the mouse forelimb]

===== Morphogen production from the dorsal ectoderm - Wnt7a=====
* name was derived from 'wingless' and 'int’
* Wnt gene first defined as a protooncogene, int1
* Humans have 19 Wnt genes
* Wnt7a gene is at 3p25 encoding a 349aa secreted glycoprotein
* patterning switch with different roles in different tissues
* One WNT receptor is called Frizzled (FZD) - named after a drosophila phenotype
* Frizzled gene family encodes a G protein-coupled receptor with 7 transmembrane domains

===Anteroposterior Axis===
* Zone of polarizing activity (ZPA)
* a mesenchymal posterior region of limb
* secretes sonic hedgehog (SHH)

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3792&rendertype=figure&id=A3815 ZPA secretes SHH and determines the anteroposterior axis of the limb bud]

=====Morphogen production from the ZPA - Sonic Hedgehog (SHH)=====

* Sonic hedgehog (SHH) is a diffusible morphogen secreted from cells, the protein product of the SHH gene
* The protein is processed by cleavage of the preprotein and addition of a palmitate molecule to the amino terminus and cholesterol to the carboxy terminus
* The SHH receptor is a cell surface protein called Patched which interacts with another cell surface protein Smoothened.
* Binding of SHH to Patched blocks its inhibitory effect on Smoothened and allows it to initiate an intracellular signaling cascade

===The Time Axis - Dynamic development and temporal gene expression===

* Different Hox genes are expressed at different times in the developing limb bud and pattern the fine structure of the limb.
* Structures are determined in a proximal>distal direction with time, i.e. proximal structures such as the humerus bone are laid down first.

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3941&rendertype=figure&id=A3956 Hox genes and dynamic patterning of the limb]

==Cellular origins of the limb==

===Limb cartilage and bone===
* Derived from local proliferating mesenchyme derived from the somatic lateral plate mesoderm (somatopleure)
* BMP2 and BMP4 play crucial roles in the development of cartilage - sufficient BMP must be present to achieve chondrogenesis. However, the main role is in later bone formation. Loss of BMP2 and 4 leads to a severe impairment of osteogenesis

[[Image:Mesoderm cartoon4.gif]]

[http://www.ncbi.nlm.nih.gov/books/NBK10085/figure/A3468/?report=objectonly - Differentiation of somitic mesoderm in the chick embryo]

===Limb muscle and dermis===
* Skeletal muscle derived from somites, the hypaxial part of the myotome
* Pax3 positive migratory myoblasts invade the limb bud
* Similarly, dermal cells also invade derived from the dermomyotome
* Both maintain the identity of the somite from which they were derived so that innervation corresponds to the same spinal nerve root.
* Note that dermatomes are rotated due to embryonic limb rotations

Origin of limb muscle cells - Migrations traced by grafting cells from a quail embryo into a chick embryo
* two species very similar in development
* quail cells recognizable by distinctive nucleoli
* Quail somite cells substituted for somite cells of 2 day chick embryo
* wing of chick sectioned a week later
* found muscle cells in chick wing derive from transplanted quail somites

Dorsal/Ventral Muscle Mass - sometimes referred to as the anterior and posterior muscle compartments. The posterior compartment of the lower hindlimb is mainly made up of the gastrocnemius muscles, the plantaris muscle and the soleus muscle.

Forelimb Muscles

Limb Muscle - Differentiation of Skeletal muscle is the same as in the myotome blocks but involves an extra migratory step

# Muscle precursor cells migrate to the muscle location
# Form beds of proliferating myoblasts
# Myoblasts fuse together to form a syncitial structure called a myotube
# Myotubes begin to express contractile proteins, form sarcomeres
# mature into myofibers with tendon connections at each end, motor and sensory innervation.

==Hand and Footplates==
[[File:BMP syndactyly.jpg|thumb|Depletion of BMP Signaling Causes Interdigital Syndactyly]]
* 5th week- hand and footplates appear at the ends of limb buds and ridges form digital rays
* Cells between the digital rays are removed by programmed cell death (apoptosis)
* 3-5 day difference between hand and foot development

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb024.htm hand growth]

===Apoptosis===

[http://php.med.unsw.edu.au/cellbiology/index.php?title=2009_Lecture_18 Cell Biology - Apoptosis Lecture]

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3245&rendertype=figure&id=A3246 Fluorescent staining of cells undergoing apoptosis in the limb]

==Limb Rotation==
[[File:Stage20-23 limbs a.jpg|thumb]]
* 8th week limbs rotate in different directions (Humans Stage 20-23)
* thumb and toe rostral
* knee and elbow face outward
* '''upper limb rotates dorsally'''
* '''lower limb rotates ventrally'''

==Limb Innervation==
[[File:Gray0807.gif|thumb|brachial plexus]]
[[File:Dermatomes.png|thumb|Adult Dermatomes]]
* spinal cord segmental nerves form a plexus adjacent to each limb
* Brachial (upper) lumbar (lower)
* Plexus forms as nerves invade the limb bud mesechyme
* Fetal period - touch pads become visible on hands and feet

[http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb019.htm brachial plexus origin]

==Limb Abnormalities==

===Congenital Hip Dislocation===
[[File:Congenital dislocation hip.jpg|thumb|Congenital Hip Dislocation]]
* Instability of the femoral head in the acetabulum - ligaments may stretch: 1:60 at birth
* congenital instability of hip, later dislocates by muscle pulls or gravity
* familial predisposition female predominance
* Growth of femoral head, acetabulum and innominate bone are delayed until the femoral head fits firmly into the acetabulum

[http://embryology.med.unsw.edu.au/Notes/skmus72.htm limb abnormalities]

===Maternal===
* thalidomide Phocomelia
* short ill-formed upper or lower limbs
* hyperthermia

===Genetic===
* Trisomy 21 - Downs syndrome [[File:Trisomy21_hand.jpg|thumb]]
* Human Gene Mutations - mutation of any of the patterning genes will result in limb abnormalities
Type II syndactyly- HoxD13

===Muscle Development===
Duchenne Muscular Dystrophy
* X-linked dystrophy
* large gene encoding cytoskeletal protein- Dystrophin
* progressive wasting of muscle, die late teens

Becker Muscular Dystrophy
* milder form, adult onset

==Online Links==
* UNSW Embryology [http://embryology.med.unsw.edu.au/Notes/skmus7.htm Limb Development]
* Embryo Images [http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimbtoc.htm Limb Unit]
* International J. Dev. Biology Vol 46 [http://www.ijdb.ehu.es/0207contents.htm Special Issue- Limb Development 2002]
* Research Labs - [http://pages.unibas.ch/anatomie/zeller/seiten/seite1.html Rolf Zeller University of Basel Medical School]

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West -

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3928 Formation of the Limb Bud] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3941 Generating the Proximal-Distal Axis of the Limb]

* '''Molecular Biology of the Cell''' Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=limb_development&rid=mboc4.figgrp.3815 Figure 21-13. Sonic hedgehog as a morphogen in chick limb development]

* '''Madame Curie Bioscience Database''' Chapters taken from the Madame Curie Bioscience Database (formerly, Eurekah Bioscience Database)

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=limb_development limb development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=limb_development limb development]

==Images==
===Stage13===
[[File:Stage13 bf1c.jpg]] [[File:Stage13 sem1c.jpg]]
===Stage14===
[[File:Stage14_bf2cl.jpg]] [[File:Stage14_sem1c.jpg]]

{{Glossary}}
{{Footer}}

Lecture - Musculoskeletal Development

2013-09-11T05:19:38Z

Z3283213:

== Introduction ==
[[File:Axial skeleton.jpg|thumb|400px]]
This lecture is an introduction to the process of musculoskeletal development. In the body, this is mainly about '''mesoderm''' differentiation beginning with an embryonic connective tissue structure, the '''mesenchyme'''. In the head, this is a mixture of mesoderm and neural crest differentiation, from mesenchyme and ectomesenchyme respectively. The lecture will cover mainly cartilage and bone, as muscle will be covered in the limb lecture and in this week's laboratory.

Note that genes that control skeleton patterning and cell differentiation are different.

==Lecture Objectives==
[[File:Stage14_sem1c.jpg|thumb|Embryo stage 14 SEM]]

* Understanding of mesoderm and neural crest development.
* Understanding of connective tissue development.
* Understanding of muscle, cartilage and bone development.
* Understanding of the two forms of bone development.
* Brief understanding of bone molecular development.
* Brief understanding of other bone roles.
* Brief understanding of bone abnormalities.

==Information==

Lecture Date: 2013-09-17 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document

The audio will be available via the Lectopia system through Blackboard

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00014-X&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00014-X Chapter 14 - Skeletal System]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00015-1&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00015-1 Chapter 15 - Muscular System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009.

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10008-9 Chapter 8 - Development of the Musculoskeletal System]
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Musculoskeletal Links}}
|}

:'''Links:''' [[Embryology_Textbooks_-_UNSW|UNSW Textbooks]] | [[Embryology Textbooks]]

==Musculoskeletal medical conditions==

[http://www.aihw.gov.au/publications/index.cfm/title/10699 Health expenditure for arthritis and musculoskeletal conditions, 2004-05]

:"Arthritis and musculoskeletal conditions affect more than 6 million Australians. In 2004-05, direct health expenditure on these conditions amounted to $4.0 billion or 7.5% of total allocated health expenditure in Australia."

[http://geneticsf.labanca.net/?p=771 Craniofacial abnormalities in Williams-Beuren syndrome]

Williams-Beuren syndrome is a genetic disease caused by a hemizygous deletion of 28 genes on chromosome 7. Leads to a distinctive set of craniofacial features. Probably caused by defects in patterning rather than differentiation as all of the structures form normally, just in slightly different positions relative to each other.
[http://www.med.unsw.edu.au/SOMSWeb.nsf/page/Neuromuscular%20and%20Regenerative%20Medicine%20Unit Neuromuscular and regenerative medicine unit, SOMS]

==Anterior-Posterior (A/P) Patterning of the axial musculoskeletal system==
[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3881 Expression of the Hox genes defines locations on the anteroposterior axis]

The hox gene clusters control anteroposterior (A/P) patterning to provide positional clues for the development of specific structures e.g. cervical, thoracic, lumbar and sacral vertebrae.

== Patterning and differentiation of the somitic mesoderm ==

[[Image:Mesoderm cartoon4.gif]]

===Sclerotome===
[[File:Somite_cartoon3.png]][[File:Somite_cartoon4.png]][[File:Somite_cartoon5.png]]

The notochord is an ancient evolutionary structure that forms a rigid A/P rod in chordate animals - chordates are ancestors of vertebrates including humans

[http://www.ncbi.nlm.nih.gov/books/NBK10085/figure/A3468/?report=objectonly - Differentiation of somitic mesoderm in the chick embryo]

==Neural Crest Derived Cells==

[http://www.ncbi.nlm.nih.gov/books/NBK10065/figure/A3111/?report=objectonly Migration and tissue contribution of neural crest cells in the chick embryo]

Neural crest-derived cells are essential to form the bones and cartilage of the face and neck, it also forms the cranial nerves and pigment cells, dorsal root ganglia and the sympathetic neurons.

==Making an Embryonic Cartilage Model==

Stage 1 - Signalling interactions between mesenchyme and an epithelial population

Stage 2 - Cell Condensation - mesenchymal dispersed cell population, gathers together to differentiate

Stage 3 - Overt Differentiation

[[File:Endochondral ossification.jpg|thumb]]
[[File:Developing vertebra.jpg|thumb]]

[http://www.mdconsult.com/books/figure.do?figure=true&eid=4-u1.0-B978-1-4160-3706-4..50017-7--f3&sectionEid=4-u1.0-B978-1-4160-3706-4..50017-7&isbn=978-1-4160-3706-4&uniqId=281144369-2 Stages of Cartilage Differentiation]

[http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Cartilage/Cartil.htm Histology - Cartilage]

===Development of Vertebrae===
[[File:Gray0082.jpg|thumb]]
* Vertebral column formation - week 4, somite sclerotome surrounds notochord.
** notochord (and floorplate) induces sclerotome migration and vertebral body cartilages.
** neural tube induces vertebral arches.
* Scleretome has 2 components
** Rostral (upper) loose and a caudal (lower) compact

[[File:Gray0065.jpg|500px]] [http://embryology.med.unsw.edu.au/Movies/mesoderm/vertabra3.mov Vertebra]
* Vertebral segmentation is shifted 1/2 somite caudally - by fusion rostral compact with caudal loose to form vertebra from 2 sclerotomes.
** This allows (i) the segmental spinal nerves to emerge between the vertebral bodies (at the same level as the intervertebral discs) (ii) the somite-derived muscle masses to interconnect between the intervertebral joints.

* Caudal dense region also forms neural arch.

Adult vertebral column
* 33 total - 7 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 5 coccygeal

====Intervertebral Disc====
* Structure - annulus and nucleus pulposus
* dense region of sclerotome.
* notochord initially contributes to nucleus pulposus of each disc, contribution replaced and lost postnatally.

====Ribs====
[[File:Gray0067.png|thumb|vertebra origin: body, arch, and costal process]]
* dense region of sclerotome contributes costal processes (thoracic region).
** chondrification commences day 45 and rib cage is cartilage by end of embryonic period.

====Sternum====

* mesenchyme from ventral body wall (manubrium, body, ziphoid).
* sternal cartilage "bars" fuse with costal processes and developing clavicles by end of embryonic period.

===Cartilage growth===
[http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Cartilage/Cartil.htm Histology - Cartilage]
* Interstitial growth - occurs mainly in immature cartilage. Chondroblasts in existing cartilage divide and form small groups of cells (isogenous groups) which produce matrix to become separated from each other by a thin partition of matrix.
* Appositional growth - occurs also in mature cartilage. Mesenchymal cells surrounding the cartilage in the deep part of the perichondrium (or the chondrogenic layer) differentiate into chondroblasts.

===Hypertrophic Chondrocytes===
* secrete VEGF, promoting vascular invasion
* hypertrophic calcified cartilage becomes resorbed, by recruited chondroclasts/osteoclasts via MMP9

== Formation of Bone ==
[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3479&rendertype=figure&id=A3482 Mice lacking Cbfa1 (Runx2) don't form bone]

[[File:Endochondral bone.jpg|300px|left]]
* Two major systems of bones: the axial skeleton and the appendicular skeleton.
** axial skeleton - 80 bones (skull, vertebrae, ribs, and sternum)
** appendicular skeleton - 126 bones (shoulders, pelvis, and limbs)

* Two main forms of bone formation: Endochondral and Intramembranous. Ossification process continues postnatally through puberty until mid 20s.

[http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Bone/Bone.htm Histology - Bone]
[[File:Periosteum.jpg|thumb]]
[[File:Gray0101.jpg|200px]][[File:Gray0118.jpg|200px]][[File:Gray0119.jpg|200px]]

===Endochondral Ossification===
[[File:Ossification endochondral 1c.jpg|thumb]]
* Majority of skeleton formed by this process (vertebra, limb long bones)
* Osteoblasts derived from the bone collar replace cartilage matrix with a matrix rich in type I collagen leading to bone formation
* Ossification centres (primary and secondary)
* Early ossification occurs at ends of long bone
[http://www.ncbi.nlm.nih.gov/books/NBK10056/figure/A3484/?report=objectonly - Diagram of ossification in long bone]
[http://www.e-radiography.net/articles/ossification/ossification.htm University of Bristol - ossification]

===Intramembranous ossification in the turtle - a model system===
[http://www.ncbi.nlm.nih.gov/books/NBK10056/figure/A3481/?report=objectonly - Intramembranous ossification]

===Intramembranous Ossification in the skull vault===
[[File:Fetal head medial.jpg|300px]][[File:Fetal head lateral.jpg|300px]]
[[File:Ossification centre.jpg|thumb]]

* Specialized form of ossification from a mesenchymal membrane. (skull and clavicle)- Neural crest-derived mesenchymal cells proliferate - some cells differentiate to form blood vessels, others become osteoblasts and begin secreting collagen-proteoglycan matrix that can bind calcium salts.

====Skull====
[[File:Human skull lateral simplified.png|thumb|skull bones]]
[[File:Fetal head section.jpg|thumb|12 week fetal head]]
The Skull is a unique skeletal structure in several ways: embryonic cellular origin (neural crest), form of ossification (intramembranous and endochondrial) and flexibility (fibrous sutures). [http://embryology.med.unsw.edu.au/Notes/skmus8a.htm Musculoskeletal Development - Skull Development]

The bones enclosing the brain have large flexible fibrous joints (sutures) which allow firstly the head to compress and pass through the birth canal and secondly to postnatally expand for brain growth.

These sutures gradually fuse at different times postnatally, firstly the metopic suture in infancy and the others much later. Abnormal fusion (synostosis) of any of the sutures will lead to a number of different skull defects.

===Osteogenesis===

* Osteoprogenitor cell - periosteum and endosteum
* Osteoblast - Secrete bone matrix, differentiate into osteocytes
* Osteocyte - Mature bone cell, Embedded in matrix, matrix calcifies soon after deposition

===Osteoclastogenesis===
* Formation of mature osteoclasts involved in bone resorption - the osteoblasts regulate this process through the production of RANKL (Receptor Activator for Nuclear Factor κ B Ligand) which is found on the cell surface of osteoblasts. RANKL is a key player in rheumatoid arthritis.

Osteoclast origin- fusion of monocytes or macrophages, Blood macrophage precursor, Attach to bone matrix - very large cells containing 15-20 nucleii.

Lysosomes - released into space between ruffled border and bone matrix, enzymes break down collagen fibres, resorption bays or Howship's lacunae

== Muscle ==
[http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Muscle/Muscle.htm Histology - Muscle]

===Myogenesis===

* Smooth muscle - cells originate from undifferentiated mesenchymal cells. These cells differentiate first into mitotically active cells, myoblasts, which contain a few myofilaments. Myoblasts give rise to the cells which will differentiate into mature smooth muscle cells.

* Skeletal muscle - cells originate from the paraxial mesoderm. Myoblasts undergo frequent divisions and coalesce with the formation of a multinucleated, syncytial muscle fibre or myotube. The nuclei of the myotube are still located centrally in the muscle fibre. In the course of the synthesis of the myofilaments/myofibrils, the nuclei are gradually displaced to the periphery of the cell.

* Cardiac muscle - cells originate from the prechordal splanchnic mesoderm.

===Skeletal Muscle Stages===

'''Myoblast''' - individual progenitor cells

'''Myotube''' - multinucleated, but undifferentiated contractile apparatus (sarcomere)

'''Myofibre''' (myofiber, muscle cell) - multinucleated and differentiated sarcomeres
* primary myofibres - first-formed myofibres, act as a structural framework upon which myoblasts proliferate, fuse in linear sequence
* secondary myofibers - second later population of myofibres that form surrounding the primary fibres.

'''Muscle Fibre Types'''
* type IIB, IIA, IIX, and I fibres - based only on the myosin ATPase activity.
** Type I fibres appear red, due to the presence of myoglobin
** Type II fibres appear white, due to the absence of myoglobin and their glycolytic nature.
* A group of individual myofibres within a muscle will be innervated by a single motor neuron.
* The electrical properties of the motor neuron will regulate the contractile properties of all associated myofibres.

'''MH-''' you do not need to know the table below in detail, it is provided for information purposes only.

{|class="wikitable"
|-
!bgcolor="LightSteelBlue"|Fibre Type ||bgcolor="LightSteelBlue"|Type I fibres ||bgcolor="LightSteelBlue"|Type II a fibres ||bgcolor="LightSteelBlue"|Type II x fibres ||bgcolor="LightSteelBlue"|Type II b fibres
|-
|Contraction time ||Slow ||Moderately Fast ||Fast ||Very fast
|-
|Size of motor neuron ||Small ||Medium ||Large ||Very large
|-
|Resistance to fatigue ||High || Fairly high ||Intermediate ||Low
|-
|Activity Used for ||Aerobic ||Long-term anaerobic ||Short-term anaerobic ||Short-term anaerobic
|-
|Maximum duration of use ||Hours||<30 minutes||<5 minutes||<1 minute
|-
|Power produced ||Low ||Medium ||High ||Very high
|-
|Mitochondrial density ||High ||High ||Medium ||Low
|-
|Capillary density ||High ||Intermediate ||Low ||Low
|-
|Oxidative capacity ||High ||High ||Intermediate ||Low
|-
|Glycolytic capacity ||Low ||High ||High ||High
|-
|Major storage fuel ||Triglycerides ||Creatine phosphate, glycogen ||Creatine phosphate, glycogen ||Creatine phosphate, glycogen
|-
|Myosin heavy chain, human genes || MYH7 || MYH2 ||MYH1 || MYH4
|}

===Myotome===

This term is used to describe the region of the somite that contributes skeletal muscle to the embryo body. Each somite pair level gives rise to a group of skeletal muscles supplied by a specific segmental spinal nerve. The muscle arises from a specific somite and the spinal nerve arises from a specific level of the spinal cord (identified by vertebral column).

In humans this corresponds to the following spinal nerves (from top to bottom) and muscular functions:
* C3,4 and 5 supply the diaphragm for breathing.
* C5 supply shoulder muscles and muscles to bend our elbow.
* C6 for bending the wrist back.
* C7 for straightening the elbow.
* C8 bends the fingers.
* T1 spreads the fingers.
* T1 –T12 supplies the chest wall and abdominal muscles.
* L2 bends the hip.
* L3 straightens the knee.
* L4 pulls the foot up.
* L5 wiggles the toes.
* S1 pulls the foot down.
* S3,4 and 5 supply the bladder, bowel, sex organs, anal and other pelvic muscles.

==Puberty==
* Musculoskeletal mass doubles by the end of puberty
* regulated growth by - sex steroid hormones, growth hormone, insulin-like growth factors
* accumulation of (peak) bone mass during puberty relates to future osteoporosis in old age

==Abnormalities==
Additional abnormalities will be covered in the limb development lecture. [http://embryology.med.unsw.edu.au/Notes/skmus2.htm see also Musculoskeletal Abnormalities]
[[File:Australian abnormalities graph allsystem.png|300px]][[File:Australian abnormalities pie skmus.png|300px]]
===Bone===
====Vertebra====
* Spina Bifida - neural tube failure to close, disrupts neural arch formation
* Block vertebra - failure of vertebra separation, lumbar region, chrondrification abnormality
* Klippel-Feil Syndrome - non-segmented cervical vertebra, more female
* see also [[#scoliosis|scoliosis]]

====Rib====
* Accessory rib (extra rib cervical or lumbar uni- or bilateral), short-rib polydactyly syndrome (lethal, chondroplasia), pigeon chest (rib overgrowth), funnel chest (sternum depression and lower costal cartilages)

====Osteogenesis Imperfecta====
* brittle-bone syndrome
* abnormal collagen type I, fail to assemble triple helix, degrade imperfect collagen, leads to fragile bones

====Scoliosis====
[[File:Scoliosis.jpg]][[File:Scoliosis xray.jpg]]
* assymetric growth impairment of vertebral bodies
* lateral deviation of spine (Lateral flexion, Forward flexion, Rotation of vertebral column on long axis)
* compensated by movement of vertebral column above and below affected region (producing a primary and two secondary curves)
* progresses rapidly in adolescence and becomes fixed once bone growth is completed.

====Congenital Hip Dislocation====
[[File:Congenital dislocation hip.jpg|thumb|Congenital Hip Dislocation]]
* Instability: 1:60 at birth; 1:240 at 1 wk: Dislocation untreated; 1:700
* congenital instability of hip, later dislocates by muscle pulls or gravity
* familial predisposition female predominance
* Growth of femoral head, acetabulum and innominate bone are delayed until the femoral head fits firmly into the acetabulum

===Muscle===

'''MH''' - Covered in next lecture and lab.
====Congenital Myopathies====

====Muscular Dystrophy====
[http://embryology.med.unsw.edu.au/Notes/skmus2.htm#Muscular%20Dystrophy Muscular Dystrophy]

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter Chapter 10 The Pharyngeal Apparatus pp201 - 240.
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 12 Development of the Head, the Neck, the Eyes, and the Ears pp349 - 418.

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.chapter.3450 Paraxial and intermediate mesoderm] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3475 Myogenesis: The Development of Muscle] | [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=dbio.section.3479 Osteogenesis: The Development of Bones] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.figgrp.3478 Figure 14.10. Conversion of myoblasts into muscles in culture]

* '''Molecular Biology of the Cell''' Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=mboc4.TOC&depth=2 Search Molecular Biology of the Cell][http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.section.4177#4187 Bone Is Continually Remodeled by the Cells Within It][http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.figgrp.4191 Image: Figure 22-52. Deposition of bone matrix by osteoblasts.][http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.figgrp.4196 Image: Figure 22-56. The development of a long bone.]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=mesoderm mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=somite somite] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=myogenesis myogenesis] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=chondrogenesis chondrogenesis] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=osteogenesis osteogenesis]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=mesoderm mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=somite somite] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=myogenesis myogenesis] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=chondrogenesis chondrogenesis] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=osteogenesis osteogenesis]

== UNSW Embryology Links ==
* '''Notes:''' [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Bone Development] | [http://embryology.med.unsw.edu.au/Notes/skmus7.htm Limb Development] | [http://embryology.med.unsw.edu.au/Notes/skmus8.htm Axial Skeleton Development] | [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Bone Development] | [http://embryology.med.unsw.edu.au/Notes/skmus8a.htm Skull | Development] [http://embryology.med.unsw.edu.au/Notes/skmus7.htm Limb] | [http://embryology.med.unsw.edu.au/Notes/skmus8.htm Axial Skeleton]| [http://embryology.med.unsw.edu.au/Notes/skmus9a.htm Human Bone] | [http://embryology.med.unsw.edu.au/Notes/skmus9b.htm Endochondral Ossification] | [http://embryology.med.unsw.edu.au/Notes/skmus12.htm Skeletal Muscle] | [http://embryology.med.unsw.edu.au/Notes/skmus30.htm Cartilage] | [http://embryology.med.unsw.edu.au/Notes/skmus31.htm Joints]

* '''Lectures:''' [http://embryology.med.unsw.edu.au/Science/ANAT2341lecture16.htm ANAT2341 - Embryology 2008 - Lecture 16]
* '''Movies:''' [http://embryology.med.unsw.edu.au/Movies/mesoderm.htm Mesoderm Movies] | [http://embryology.med.unsw.edu.au/Movies/mesoderm/somite2.mov Somite - Myotome body wall] | [http://embryology.med.unsw.edu.au/Movies/mesoderm/vertabra3.mov Vertebra]

== External Links ==

* '''UWA Blue Histology''' [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Muscle/Muscle.htm Skeletal Tissues - Muscle] | [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Cartilage/Cartil.htm Skeletal Tissues -Cartilage] | [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Bone/Bone.htm Skeletal Tissues - Bone]

* '''University of Kansas Histoweb''' [http://www.kumc.edu/instruction/medicine/anatomy/histoweb/bone/bone.htm Bone]

* '''Loyola University Medical Education Network''' [http://www.lumen.luc.edu/lumen/MedEd/Histo/frames/h_frame9.html Part 9: Specialized Connective Tissue: Cartilage and Bone] | [http://www.lumen.luc.edu/lumen/MedEd/Histo/frames/h_frame10.html Part 10: Endochondral Ossification]

* '''UNSW Embryology''' [http://embryology.med.unsw.edu.au/histology/cartilagebone/cartbone1.html Cartilage and Bone]

* '''University of Bristol''' [http://www.e-radiography.net/articles/ossification/ossification.htm ossification]

== Terms ==
'''annulus fibrosus -''' the circularly arranged fibers (derived from sclerotome)that together with the nucleus pulposus (derived from notochord) form the [[#intervertebral disc|intervertebral disc]] (IVD) of the vertebral column.

'''axial mesoderm -''' (=notochord)

'''cartilage -''' connective tissue from mesoderm in the embryo forms the initial skeleton which is replaced by bone. In adult, found on surface of bone joints.

'''Cbfa1''' - Core-Binding Factor 1 (Runx2) transcription factor protein key to the differentiation of bone [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600211 OMIM: Cbfa1]

'''centrum -''' the primordium of the [[#vertebral body|vertebral body]] formed initially by the sclerotome.

'''clavicle -''' (Latin, ''clavicle'' = little key) bone which locks shoulder to body.

'''dermatome -'''

'''dermomyotome''' - dorsolateral half of each somite that forms the dermis and muscle.

'''ectoderm -''' the layer (of the 3 germ cell layers) which form the nervous system from the neural tube and neural crest and also generates the epithelia covering the embryo.

'''endochondrial ossification -''' the process of replacement of the cartilagenous framework by osteoblasts with bone.

'''epaxial myotome -''' the dorsal portion of the myotome that generates dorsal skeletal muscles (epaxial muscles), which include other muscles associated with the vertebrae, ribs, and base of the skull.

'''extracellular matrix -''' material secreted by and surrounding cells. Consists if fibers and ground substance.

'''fibroblast growth factors -''' (FGF) a family of at least 10 secreted proteins that bind membrane tyrosine kinase receptors. A patterning switch with many different roles in different tissues. (FGF8 = androgen-induced growth factor (AIGF)

'''fibroblast growth factor receptor - '''receptors comprise a family of at least 4 related but individually distinct tyrosine kinase receptors (FGFR1- 4). They have a similar protein structure, with 3 immunoglobulin-like domains in the extracellular region, a single membrane spanning segment, and a cytoplasmic tyrosine kinase domain.

'''growth factor -''' usually a protein or peptide that will bind a cell membrane receptor and then activates an intracellular signaling pathway. The function of the pathway will be to alter the cell directly or indirectly by changing gene expression. (eg shh)

'''hox -''' (='''h'''omeob'''ox''') family of transcription factors that bind DNA and activate gene expression. Expression of different Hox genes along neural tube defines rostral-caudal axis and segmental levels.

'''hypaxial myotome -''' the ventral portion of the myotome that generates ventral skeletal muscles (hypaxial muscles) which include some vertebral muscles, the diaphragm, the abdominal muscles, and all limb muscles.

'''intercostal-''' the region between adjacent ribs, usually comprising intercostal muscles and connective tissue.

'''intervertebral disc-''' (IVD) the annulus fibrosus+nucleus pulposus together form the intervertebral disc (IVD) of the vertebral column. This is the flexible region between each bony vertebra that allows the column to be bent.

'''lumbar plexus -''' mixed spinal nerves innervating the lower limb form a complex meshwork (crossing).

'''mesenchymal progenitor cells - ''' (MPCs) cells able to differentiate in various types of connective tissue, including cartilage, bone and adipose tissue.

'''mesoderm -''' the middle layer of the 3 germ cell layers of the embryo. Mesoderm outside the embryo and covering the amnion, yolk and chorion sacs is extraembryonic mesoderm.

'''myoblast -''' the undifferentiated mononucleated muscle cells that will fuse together to form a multinucleated myotube, then mature into a muscle fibre.

'''MyoD -''' transcription factor involved in the determination of muscle cells in the somite. A basic helix-loop-helix factor which binds DNA.

'''myotome -''' the portion of the dermamyotome that generates skeletal muscle. Has 2 components epaxial (dorsal muscles ) hypaxial (ventral muscles).

'''neural crest -''' cell region at edge of neural plate, then atop the neural folds, that remains outside and initially dorsal to the neural tube when it forms. These paired dorsal lateral streaks of cells migrate throughout the embryo and can differentiate into many different cell types(=pluripotential). Those that remain on the dorsal neural tube form the sensory spinal ganglia (DRG). Neural crest cells migrate into the somites.

'''osteoblast''' - The mesenchymal cells that differentiate to form the cellular component of bone and produce bone matrix. Mature osteoblasts are called osteocytes. (More? [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Musculoskeletal Development - Bone])

'''osteoclast''' - Cells that remove bone (bone resorption) by enzymatically eroding the bone matrix. These cells are monocyte-macrophage in origin and fuse to form a multinucleated osteoclast. These cells allow continuous bone remodelling and are also involved in calcium and phosphate metabolism. The erosion cavity that the cells lie iwithin and form is called Howship's lacuna. (More? [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Musculoskeletal Development - Bone])

'''osteocyte''' - The mature bone-forming cell, which form the cellular component of bone and produce bone matrix. Differentiate from osteoblasts, mesenchymal cells that differentiate to form bone. (More? [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Musculoskeletal Development - Bone])

'''osteon''' - The anatomical (histological) unit structure (principal structure) of compact bone. (More? [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Musculoskeletal Development - Bone])

'''Pax -''' name derived from Drosophila gene 'paired' (prd) the 'paired box' is a amino end 124 amino-acid conserved domain (signature aa 35-51: '''P-C-x(11)-C-V-S'''). Transcription factor of the helix-turn-helix structural family, DNA binding, and activating gene expression. In human, nine member proteins from Pax-1 to Pax-9. Regulate differentiation of many different tissues. Some members of the family (PAX3, PAX4, PAX6, PAX7) also contain a functional homeobox domain.

'''pedicle -''' (Latin, ''pediculus'' = small foot) part of the vertebral arch forming the segment between the transverse process and the vertebral body.

'''primary centre of ossification -''' the first area where bone growth occurs between the periosteum and cartilage.

'''sclerotome -''' ventromedial half of each somite that forms the vertebral body and intervertebral disc.

'''segmentation -''' to break a solid structure into a number of usually equal size pieces.

'''somatic mesoderm -''' derived from lateral mesoderm closest to the ectoderm and separated from other component of lateral mesoderm (splanchnic, near endoderm) by the intraembryonic coelom.

'''somite -''' segmental block (ball) of mesoderm formed from paraxial mesoderm adjacent to notochord (axial mesoderm). Differentiates to form initially sclerotome and dermamyotome (then dermotome and myotome).

'''somitic mesoderm-'''

'''somitocoel -''' a transient cavity that appears within each of the the early forming somites then is lost.

'''somitogenesis -''' the process of segmentation of the paraxial mesoderm to form "mesoderm balls" beginning cranially (humans day20) and extending caudally at 1 somite/90 minutes until approx. 44 pairs have been formed.

'''sonic hedgehog -''' (=shh) secreted growth factor that binds patched (ptc) receptor on cell membrane. SHH function is different for different tissues in the embryo. In the nervous system, it is secreted by the notochord, ventralizes the neural tube, inducing the floor plate and motor neurons. In the Limb it is secreted by the zone of polarizing activity (ZPA) organizing limb axis formation.

'''Tbx -''' T-box genes (transcription factor) involved in mouse forelimb (Tbx4) and hindlimb (Tbx5) specification.

'''transcription factor-''' a factor (protein or protein with steroid) that binds to DNA to alter gene expression, usually to activate. (eg steroid hormone+receptor, Retinoic acid+Receptor, Hox, Pax, Lim, Nkx-2.2).

'''vertebral body-''' formed by centrum, vertebral arch, facets for ribs. It is the mature vertebral structure formed by the 5 secondary ossification centers after puberty.

'''vertebral column -''' name given to the complete structure formed from the alternating segments of vertebra and intervertebral discs which support the spinal cord.

'''vertebral foramen -''' the dorsal cavity within each vertebra, generated by the vertebral arch that surrounds the spinal cord.

'''Wnt7a -''' The designation 'Wnt' was derived from 'wingless' and 'int'. The Wnt gene was first defined as a protooncogene, int1. Humans have at least 4 Wnt genes: Wnt7a gene is at 3p25 encoding a 349aa secreted glycoprotein. A patterning switch with different roles in different tissues. The mechanism of Wnt distribution (free diffusion, restricted diffusion and active transport) and all its possible cell receptors are still being determined. At least one WNT receptor is Frizzled (FZD). The Frizzled gene family encodes a seven-transmembrane receptor.

==Images==
<gallery>
File:Bone remodeling cycle.jpg|Bone remodeling cycle
</gallery>

{{Glossary}}
{{Footer}}

Lecture - Musculoskeletal Development

2013-09-11T05:16:12Z

Z3283213:

== Introduction ==
[[File:Axial skeleton.jpg|thumb|400px]]
This lecture is an introduction to the process of musculoskeletal development. In the body, this is mainly about '''mesoderm''' differentiation beginning with an embryonic connective tissue structure, the '''mesenchyme'''. In the head, this is a mixture of mesoderm and neural crest differentiation, from mesenchyme and ectomesenchyme respectively. The lecture will cover mainly cartilage and bone, as muscle will be covered in the limb lecture and in this week's laboratory.

Note that genes that control skeleton patterning and cell differentiation are different.

==Lecture Objectives==
[[File:Stage14_sem1c.jpg|thumb|Embryo stage 14 SEM]]

* Understanding of mesoderm and neural crest development.
* Understanding of connective tissue development.
* Understanding of muscle, cartilage and bone development.
* Understanding of the two forms of bone development.
* Brief understanding of bone molecular development.
* Brief understanding of other bone roles.
* Brief understanding of bone abnormalities.

Lecture Date: 2013-09-17 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document

The audio will be available via the Lectopia system through Blackboard

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00014-X&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00014-X Chapter 14 - Skeletal System]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00015-1&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00015-1 Chapter 15 - Muscular System]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009.

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10008-9 Chapter 8 - Development of the Musculoskeletal System]
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Musculoskeletal Links}}
|}

:'''Links:''' [[Embryology_Textbooks_-_UNSW|UNSW Textbooks]] | [[Embryology Textbooks]]

==Musculoskeletal medical conditions==

[http://www.aihw.gov.au/publications/index.cfm/title/10699 Health expenditure for arthritis and musculoskeletal conditions, 2004-05]

:"Arthritis and musculoskeletal conditions affect more than 6 million Australians. In 2004-05, direct health expenditure on these conditions amounted to $4.0 billion or 7.5% of total allocated health expenditure in Australia."

[http://geneticsf.labanca.net/?p=771 Craniofacial abnormalities in Williams-Beuren syndrome]

Williams-Beuren syndrome is a genetic disease caused by a hemizygous deletion of 28 genes on chromosome 7. Leads to a distinctive set of craniofacial features. Probably caused by defects in patterning rather than differentiation as all of the structures form normally, just in slightly different positions relative to each other.
[http://www.med.unsw.edu.au/SOMSWeb.nsf/page/Neuromuscular%20and%20Regenerative%20Medicine%20Unit Neuromuscular and regenerative medicine unit, SOMS]

==Anterior-Posterior (A/P) Patterning of the axial musculoskeletal system==
[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A3871&rendertype=figure&id=A3881 Expression of the Hox genes defines locations on the anteroposterior axis]

The hox gene clusters control anteroposterior (A/P) patterning to provide positional clues for the development of specific structures e.g. cervical, thoracic, lumbar and sacral vertebrae.

== Patterning and differentiation of the somitic mesoderm ==

[[Image:Mesoderm cartoon4.gif]]

===Sclerotome===
[[File:Somite_cartoon3.png]][[File:Somite_cartoon4.png]][[File:Somite_cartoon5.png]]

The notochord is an ancient evolutionary structure that forms a rigid A/P rod in chordate animals - chordates are ancestors of vertebrates including humans

[http://www.ncbi.nlm.nih.gov/books/NBK10085/figure/A3468/?report=objectonly - Differentiation of somitic mesoderm in the chick embryo]

==Neural Crest Derived Cells==

[http://www.ncbi.nlm.nih.gov/books/NBK10065/figure/A3111/?report=objectonly Migration and tissue contribution of neural crest cells in the chick embryo]

Neural crest-derived cells are essential to form the bones and cartilage of the face and neck, it also forms the cranial nerves and pigment cells, dorsal root ganglia and the sympathetic neurons.

==Making an Embryonic Cartilage Model==

Stage 1 - Signalling interactions between mesenchyme and an epithelial population

Stage 2 - Cell Condensation - mesenchymal dispersed cell population, gathers together to differentiate

Stage 3 - Overt Differentiation

[[File:Endochondral ossification.jpg|thumb]]
[[File:Developing vertebra.jpg|thumb]]

[http://www.mdconsult.com/books/figure.do?figure=true&eid=4-u1.0-B978-1-4160-3706-4..50017-7--f3&sectionEid=4-u1.0-B978-1-4160-3706-4..50017-7&isbn=978-1-4160-3706-4&uniqId=281144369-2 Stages of Cartilage Differentiation]

[http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Cartilage/Cartil.htm Histology - Cartilage]

===Development of Vertebrae===
[[File:Gray0082.jpg|thumb]]
* Vertebral column formation - week 4, somite sclerotome surrounds notochord.
** notochord (and floorplate) induces sclerotome migration and vertebral body cartilages.
** neural tube induces vertebral arches.
* Scleretome has 2 components
** Rostral (upper) loose and a caudal (lower) compact

[[File:Gray0065.jpg|500px]] [http://embryology.med.unsw.edu.au/Movies/mesoderm/vertabra3.mov Vertebra]
* Vertebral segmentation is shifted 1/2 somite caudally - by fusion rostral compact with caudal loose to form vertebra from 2 sclerotomes.
** This allows (i) the segmental spinal nerves to emerge between the vertebral bodies (at the same level as the intervertebral discs) (ii) the somite-derived muscle masses to interconnect between the intervertebral joints.

* Caudal dense region also forms neural arch.

Adult vertebral column
* 33 total - 7 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 5 coccygeal

====Intervertebral Disc====
* Structure - annulus and nucleus pulposus
* dense region of sclerotome.
* notochord initially contributes to nucleus pulposus of each disc, contribution replaced and lost postnatally.

====Ribs====
[[File:Gray0067.png|thumb|vertebra origin: body, arch, and costal process]]
* dense region of sclerotome contributes costal processes (thoracic region).
** chondrification commences day 45 and rib cage is cartilage by end of embryonic period.

====Sternum====

* mesenchyme from ventral body wall (manubrium, body, ziphoid).
* sternal cartilage "bars" fuse with costal processes and developing clavicles by end of embryonic period.

===Cartilage growth===
[http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Cartilage/Cartil.htm Histology - Cartilage]
* Interstitial growth - occurs mainly in immature cartilage. Chondroblasts in existing cartilage divide and form small groups of cells (isogenous groups) which produce matrix to become separated from each other by a thin partition of matrix.
* Appositional growth - occurs also in mature cartilage. Mesenchymal cells surrounding the cartilage in the deep part of the perichondrium (or the chondrogenic layer) differentiate into chondroblasts.

===Hypertrophic Chondrocytes===
* secrete VEGF, promoting vascular invasion
* hypertrophic calcified cartilage becomes resorbed, by recruited chondroclasts/osteoclasts via MMP9

== Formation of Bone ==
[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A3479&rendertype=figure&id=A3482 Mice lacking Cbfa1 (Runx2) don't form bone]

[[File:Endochondral bone.jpg|300px|left]]
* Two major systems of bones: the axial skeleton and the appendicular skeleton.
** axial skeleton - 80 bones (skull, vertebrae, ribs, and sternum)
** appendicular skeleton - 126 bones (shoulders, pelvis, and limbs)

* Two main forms of bone formation: Endochondral and Intramembranous. Ossification process continues postnatally through puberty until mid 20s.

[http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Bone/Bone.htm Histology - Bone]
[[File:Periosteum.jpg|thumb]]
[[File:Gray0101.jpg|200px]][[File:Gray0118.jpg|200px]][[File:Gray0119.jpg|200px]]

===Endochondral Ossification===
[[File:Ossification endochondral 1c.jpg|thumb]]
* Majority of skeleton formed by this process (vertebra, limb long bones)
* Osteoblasts derived from the bone collar replace cartilage matrix with a matrix rich in type I collagen leading to bone formation
* Ossification centres (primary and secondary)
* Early ossification occurs at ends of long bone
[http://www.ncbi.nlm.nih.gov/books/NBK10056/figure/A3484/?report=objectonly - Diagram of ossification in long bone]
[http://www.e-radiography.net/articles/ossification/ossification.htm University of Bristol - ossification]

===Intramembranous ossification in the turtle - a model system===
[http://www.ncbi.nlm.nih.gov/books/NBK10056/figure/A3481/?report=objectonly - Intramembranous ossification]

===Intramembranous Ossification in the skull vault===
[[File:Fetal head medial.jpg|300px]][[File:Fetal head lateral.jpg|300px]]
[[File:Ossification centre.jpg|thumb]]

* Specialized form of ossification from a mesenchymal membrane. (skull and clavicle)- Neural crest-derived mesenchymal cells proliferate - some cells differentiate to form blood vessels, others become osteoblasts and begin secreting collagen-proteoglycan matrix that can bind calcium salts.

====Skull====
[[File:Human skull lateral simplified.png|thumb|skull bones]]
[[File:Fetal head section.jpg|thumb|12 week fetal head]]
The Skull is a unique skeletal structure in several ways: embryonic cellular origin (neural crest), form of ossification (intramembranous and endochondrial) and flexibility (fibrous sutures). [http://embryology.med.unsw.edu.au/Notes/skmus8a.htm Musculoskeletal Development - Skull Development]

The bones enclosing the brain have large flexible fibrous joints (sutures) which allow firstly the head to compress and pass through the birth canal and secondly to postnatally expand for brain growth.

These sutures gradually fuse at different times postnatally, firstly the metopic suture in infancy and the others much later. Abnormal fusion (synostosis) of any of the sutures will lead to a number of different skull defects.

===Osteogenesis===

* Osteoprogenitor cell - periosteum and endosteum
* Osteoblast - Secrete bone matrix, differentiate into osteocytes
* Osteocyte - Mature bone cell, Embedded in matrix, matrix calcifies soon after deposition

===Osteoclastogenesis===
* Formation of mature osteoclasts involved in bone resorption - the osteoblasts regulate this process through the production of RANKL (Receptor Activator for Nuclear Factor κ B Ligand) which is found on the cell surface of osteoblasts. RANKL is a key player in rheumatoid arthritis.

Osteoclast origin- fusion of monocytes or macrophages, Blood macrophage precursor, Attach to bone matrix - very large cells containing 15-20 nucleii.

Lysosomes - released into space between ruffled border and bone matrix, enzymes break down collagen fibres, resorption bays or Howship's lacunae

== Muscle ==
[http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Muscle/Muscle.htm Histology - Muscle]

===Myogenesis===

* Smooth muscle - cells originate from undifferentiated mesenchymal cells. These cells differentiate first into mitotically active cells, myoblasts, which contain a few myofilaments. Myoblasts give rise to the cells which will differentiate into mature smooth muscle cells.

* Skeletal muscle - cells originate from the paraxial mesoderm. Myoblasts undergo frequent divisions and coalesce with the formation of a multinucleated, syncytial muscle fibre or myotube. The nuclei of the myotube are still located centrally in the muscle fibre. In the course of the synthesis of the myofilaments/myofibrils, the nuclei are gradually displaced to the periphery of the cell.

* Cardiac muscle - cells originate from the prechordal splanchnic mesoderm.

===Skeletal Muscle Stages===

'''Myoblast''' - individual progenitor cells

'''Myotube''' - multinucleated, but undifferentiated contractile apparatus (sarcomere)

'''Myofibre''' (myofiber, muscle cell) - multinucleated and differentiated sarcomeres
* primary myofibres - first-formed myofibres, act as a structural framework upon which myoblasts proliferate, fuse in linear sequence
* secondary myofibers - second later population of myofibres that form surrounding the primary fibres.

'''Muscle Fibre Types'''
* type IIB, IIA, IIX, and I fibres - based only on the myosin ATPase activity.
** Type I fibres appear red, due to the presence of myoglobin
** Type II fibres appear white, due to the absence of myoglobin and their glycolytic nature.
* A group of individual myofibres within a muscle will be innervated by a single motor neuron.
* The electrical properties of the motor neuron will regulate the contractile properties of all associated myofibres.

'''MH-''' you do not need to know the table below in detail, it is provided for information purposes only.

{|class="wikitable"
|-
!bgcolor="LightSteelBlue"|Fibre Type ||bgcolor="LightSteelBlue"|Type I fibres ||bgcolor="LightSteelBlue"|Type II a fibres ||bgcolor="LightSteelBlue"|Type II x fibres ||bgcolor="LightSteelBlue"|Type II b fibres
|-
|Contraction time ||Slow ||Moderately Fast ||Fast ||Very fast
|-
|Size of motor neuron ||Small ||Medium ||Large ||Very large
|-
|Resistance to fatigue ||High || Fairly high ||Intermediate ||Low
|-
|Activity Used for ||Aerobic ||Long-term anaerobic ||Short-term anaerobic ||Short-term anaerobic
|-
|Maximum duration of use ||Hours||<30 minutes||<5 minutes||<1 minute
|-
|Power produced ||Low ||Medium ||High ||Very high
|-
|Mitochondrial density ||High ||High ||Medium ||Low
|-
|Capillary density ||High ||Intermediate ||Low ||Low
|-
|Oxidative capacity ||High ||High ||Intermediate ||Low
|-
|Glycolytic capacity ||Low ||High ||High ||High
|-
|Major storage fuel ||Triglycerides ||Creatine phosphate, glycogen ||Creatine phosphate, glycogen ||Creatine phosphate, glycogen
|-
|Myosin heavy chain, human genes || MYH7 || MYH2 ||MYH1 || MYH4
|}

===Myotome===

This term is used to describe the region of the somite that contributes skeletal muscle to the embryo body. Each somite pair level gives rise to a group of skeletal muscles supplied by a specific segmental spinal nerve. The muscle arises from a specific somite and the spinal nerve arises from a specific level of the spinal cord (identified by vertebral column).

In humans this corresponds to the following spinal nerves (from top to bottom) and muscular functions:
* C3,4 and 5 supply the diaphragm for breathing.
* C5 supply shoulder muscles and muscles to bend our elbow.
* C6 for bending the wrist back.
* C7 for straightening the elbow.
* C8 bends the fingers.
* T1 spreads the fingers.
* T1 –T12 supplies the chest wall and abdominal muscles.
* L2 bends the hip.
* L3 straightens the knee.
* L4 pulls the foot up.
* L5 wiggles the toes.
* S1 pulls the foot down.
* S3,4 and 5 supply the bladder, bowel, sex organs, anal and other pelvic muscles.

==Puberty==
* Musculoskeletal mass doubles by the end of puberty
* regulated growth by - sex steroid hormones, growth hormone, insulin-like growth factors
* accumulation of (peak) bone mass during puberty relates to future osteoporosis in old age

==Abnormalities==
Additional abnormalities will be covered in the limb development lecture. [http://embryology.med.unsw.edu.au/Notes/skmus2.htm see also Musculoskeletal Abnormalities]
[[File:Australian abnormalities graph allsystem.png|300px]][[File:Australian abnormalities pie skmus.png|300px]]
===Bone===
====Vertebra====
* Spina Bifida - neural tube failure to close, disrupts neural arch formation
* Block vertebra - failure of vertebra separation, lumbar region, chrondrification abnormality
* Klippel-Feil Syndrome - non-segmented cervical vertebra, more female
* see also [[#scoliosis|scoliosis]]

====Rib====
* Accessory rib (extra rib cervical or lumbar uni- or bilateral), short-rib polydactyly syndrome (lethal, chondroplasia), pigeon chest (rib overgrowth), funnel chest (sternum depression and lower costal cartilages)

====Osteogenesis Imperfecta====
* brittle-bone syndrome
* abnormal collagen type I, fail to assemble triple helix, degrade imperfect collagen, leads to fragile bones

====Scoliosis====
[[File:Scoliosis.jpg]][[File:Scoliosis xray.jpg]]
* assymetric growth impairment of vertebral bodies
* lateral deviation of spine (Lateral flexion, Forward flexion, Rotation of vertebral column on long axis)
* compensated by movement of vertebral column above and below affected region (producing a primary and two secondary curves)
* progresses rapidly in adolescence and becomes fixed once bone growth is completed.

====Congenital Hip Dislocation====
[[File:Congenital dislocation hip.jpg|thumb|Congenital Hip Dislocation]]
* Instability: 1:60 at birth; 1:240 at 1 wk: Dislocation untreated; 1:700
* congenital instability of hip, later dislocates by muscle pulls or gravity
* familial predisposition female predominance
* Growth of femoral head, acetabulum and innominate bone are delayed until the femoral head fits firmly into the acetabulum

===Muscle===

'''MH''' - Covered in next lecture and lab.
====Congenital Myopathies====

====Muscular Dystrophy====
[http://embryology.med.unsw.edu.au/Notes/skmus2.htm#Muscular%20Dystrophy Muscular Dystrophy]

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter Chapter 10 The Pharyngeal Apparatus pp201 - 240.
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 12 Development of the Head, the Neck, the Eyes, and the Ears pp349 - 418.

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.chapter.3450 Paraxial and intermediate mesoderm] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3475 Myogenesis: The Development of Muscle] | [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=dbio.section.3479 Osteogenesis: The Development of Bones] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.figgrp.3478 Figure 14.10. Conversion of myoblasts into muscles in culture]

* '''Molecular Biology of the Cell''' Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=mboc4.TOC&depth=2 Search Molecular Biology of the Cell][http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.section.4177#4187 Bone Is Continually Remodeled by the Cells Within It][http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.figgrp.4191 Image: Figure 22-52. Deposition of bone matrix by osteoblasts.][http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.figgrp.4196 Image: Figure 22-56. The development of a long bone.]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=mesoderm mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=somite somite] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=myogenesis myogenesis] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=chondrogenesis chondrogenesis] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=osteogenesis osteogenesis]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=mesoderm mesoderm] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=somite somite] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=myogenesis myogenesis] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=chondrogenesis chondrogenesis] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=osteogenesis osteogenesis]

== UNSW Embryology Links ==
* '''Notes:''' [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Bone Development] | [http://embryology.med.unsw.edu.au/Notes/skmus7.htm Limb Development] | [http://embryology.med.unsw.edu.au/Notes/skmus8.htm Axial Skeleton Development] | [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Bone Development] | [http://embryology.med.unsw.edu.au/Notes/skmus8a.htm Skull | Development] [http://embryology.med.unsw.edu.au/Notes/skmus7.htm Limb] | [http://embryology.med.unsw.edu.au/Notes/skmus8.htm Axial Skeleton]| [http://embryology.med.unsw.edu.au/Notes/skmus9a.htm Human Bone] | [http://embryology.med.unsw.edu.au/Notes/skmus9b.htm Endochondral Ossification] | [http://embryology.med.unsw.edu.au/Notes/skmus12.htm Skeletal Muscle] | [http://embryology.med.unsw.edu.au/Notes/skmus30.htm Cartilage] | [http://embryology.med.unsw.edu.au/Notes/skmus31.htm Joints]

* '''Lectures:''' [http://embryology.med.unsw.edu.au/Science/ANAT2341lecture16.htm ANAT2341 - Embryology 2008 - Lecture 16]
* '''Movies:''' [http://embryology.med.unsw.edu.au/Movies/mesoderm.htm Mesoderm Movies] | [http://embryology.med.unsw.edu.au/Movies/mesoderm/somite2.mov Somite - Myotome body wall] | [http://embryology.med.unsw.edu.au/Movies/mesoderm/vertabra3.mov Vertebra]

== External Links ==

* '''UWA Blue Histology''' [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Muscle/Muscle.htm Skeletal Tissues - Muscle] | [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Cartilage/Cartil.htm Skeletal Tissues -Cartilage] | [http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Bone/Bone.htm Skeletal Tissues - Bone]

* '''University of Kansas Histoweb''' [http://www.kumc.edu/instruction/medicine/anatomy/histoweb/bone/bone.htm Bone]

* '''Loyola University Medical Education Network''' [http://www.lumen.luc.edu/lumen/MedEd/Histo/frames/h_frame9.html Part 9: Specialized Connective Tissue: Cartilage and Bone] | [http://www.lumen.luc.edu/lumen/MedEd/Histo/frames/h_frame10.html Part 10: Endochondral Ossification]

* '''UNSW Embryology''' [http://embryology.med.unsw.edu.au/histology/cartilagebone/cartbone1.html Cartilage and Bone]

* '''University of Bristol''' [http://www.e-radiography.net/articles/ossification/ossification.htm ossification]

== Terms ==
'''annulus fibrosus -''' the circularly arranged fibers (derived from sclerotome)that together with the nucleus pulposus (derived from notochord) form the [[#intervertebral disc|intervertebral disc]] (IVD) of the vertebral column.

'''axial mesoderm -''' (=notochord)

'''cartilage -''' connective tissue from mesoderm in the embryo forms the initial skeleton which is replaced by bone. In adult, found on surface of bone joints.

'''Cbfa1''' - Core-Binding Factor 1 (Runx2) transcription factor protein key to the differentiation of bone [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600211 OMIM: Cbfa1]

'''centrum -''' the primordium of the [[#vertebral body|vertebral body]] formed initially by the sclerotome.

'''clavicle -''' (Latin, ''clavicle'' = little key) bone which locks shoulder to body.

'''dermatome -'''

'''dermomyotome''' - dorsolateral half of each somite that forms the dermis and muscle.

'''ectoderm -''' the layer (of the 3 germ cell layers) which form the nervous system from the neural tube and neural crest and also generates the epithelia covering the embryo.

'''endochondrial ossification -''' the process of replacement of the cartilagenous framework by osteoblasts with bone.

'''epaxial myotome -''' the dorsal portion of the myotome that generates dorsal skeletal muscles (epaxial muscles), which include other muscles associated with the vertebrae, ribs, and base of the skull.

'''extracellular matrix -''' material secreted by and surrounding cells. Consists if fibers and ground substance.

'''fibroblast growth factors -''' (FGF) a family of at least 10 secreted proteins that bind membrane tyrosine kinase receptors. A patterning switch with many different roles in different tissues. (FGF8 = androgen-induced growth factor (AIGF)

'''fibroblast growth factor receptor - '''receptors comprise a family of at least 4 related but individually distinct tyrosine kinase receptors (FGFR1- 4). They have a similar protein structure, with 3 immunoglobulin-like domains in the extracellular region, a single membrane spanning segment, and a cytoplasmic tyrosine kinase domain.

'''growth factor -''' usually a protein or peptide that will bind a cell membrane receptor and then activates an intracellular signaling pathway. The function of the pathway will be to alter the cell directly or indirectly by changing gene expression. (eg shh)

'''hox -''' (='''h'''omeob'''ox''') family of transcription factors that bind DNA and activate gene expression. Expression of different Hox genes along neural tube defines rostral-caudal axis and segmental levels.

'''hypaxial myotome -''' the ventral portion of the myotome that generates ventral skeletal muscles (hypaxial muscles) which include some vertebral muscles, the diaphragm, the abdominal muscles, and all limb muscles.

'''intercostal-''' the region between adjacent ribs, usually comprising intercostal muscles and connective tissue.

'''intervertebral disc-''' (IVD) the annulus fibrosus+nucleus pulposus together form the intervertebral disc (IVD) of the vertebral column. This is the flexible region between each bony vertebra that allows the column to be bent.

'''lumbar plexus -''' mixed spinal nerves innervating the lower limb form a complex meshwork (crossing).

'''mesenchymal progenitor cells - ''' (MPCs) cells able to differentiate in various types of connective tissue, including cartilage, bone and adipose tissue.

'''mesoderm -''' the middle layer of the 3 germ cell layers of the embryo. Mesoderm outside the embryo and covering the amnion, yolk and chorion sacs is extraembryonic mesoderm.

'''myoblast -''' the undifferentiated mononucleated muscle cells that will fuse together to form a multinucleated myotube, then mature into a muscle fibre.

'''MyoD -''' transcription factor involved in the determination of muscle cells in the somite. A basic helix-loop-helix factor which binds DNA.

'''myotome -''' the portion of the dermamyotome that generates skeletal muscle. Has 2 components epaxial (dorsal muscles ) hypaxial (ventral muscles).

'''neural crest -''' cell region at edge of neural plate, then atop the neural folds, that remains outside and initially dorsal to the neural tube when it forms. These paired dorsal lateral streaks of cells migrate throughout the embryo and can differentiate into many different cell types(=pluripotential). Those that remain on the dorsal neural tube form the sensory spinal ganglia (DRG). Neural crest cells migrate into the somites.

'''osteoblast''' - The mesenchymal cells that differentiate to form the cellular component of bone and produce bone matrix. Mature osteoblasts are called osteocytes. (More? [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Musculoskeletal Development - Bone])

'''osteoclast''' - Cells that remove bone (bone resorption) by enzymatically eroding the bone matrix. These cells are monocyte-macrophage in origin and fuse to form a multinucleated osteoclast. These cells allow continuous bone remodelling and are also involved in calcium and phosphate metabolism. The erosion cavity that the cells lie iwithin and form is called Howship's lacuna. (More? [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Musculoskeletal Development - Bone])

'''osteocyte''' - The mature bone-forming cell, which form the cellular component of bone and produce bone matrix. Differentiate from osteoblasts, mesenchymal cells that differentiate to form bone. (More? [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Musculoskeletal Development - Bone])

'''osteon''' - The anatomical (histological) unit structure (principal structure) of compact bone. (More? [http://embryology.med.unsw.edu.au/Notes/skmus9.htm Musculoskeletal Development - Bone])

'''Pax -''' name derived from Drosophila gene 'paired' (prd) the 'paired box' is a amino end 124 amino-acid conserved domain (signature aa 35-51: '''P-C-x(11)-C-V-S'''). Transcription factor of the helix-turn-helix structural family, DNA binding, and activating gene expression. In human, nine member proteins from Pax-1 to Pax-9. Regulate differentiation of many different tissues. Some members of the family (PAX3, PAX4, PAX6, PAX7) also contain a functional homeobox domain.

'''pedicle -''' (Latin, ''pediculus'' = small foot) part of the vertebral arch forming the segment between the transverse process and the vertebral body.

'''primary centre of ossification -''' the first area where bone growth occurs between the periosteum and cartilage.

'''sclerotome -''' ventromedial half of each somite that forms the vertebral body and intervertebral disc.

'''segmentation -''' to break a solid structure into a number of usually equal size pieces.

'''somatic mesoderm -''' derived from lateral mesoderm closest to the ectoderm and separated from other component of lateral mesoderm (splanchnic, near endoderm) by the intraembryonic coelom.

'''somite -''' segmental block (ball) of mesoderm formed from paraxial mesoderm adjacent to notochord (axial mesoderm). Differentiates to form initially sclerotome and dermamyotome (then dermotome and myotome).

'''somitic mesoderm-'''

'''somitocoel -''' a transient cavity that appears within each of the the early forming somites then is lost.

'''somitogenesis -''' the process of segmentation of the paraxial mesoderm to form "mesoderm balls" beginning cranially (humans day20) and extending caudally at 1 somite/90 minutes until approx. 44 pairs have been formed.

'''sonic hedgehog -''' (=shh) secreted growth factor that binds patched (ptc) receptor on cell membrane. SHH function is different for different tissues in the embryo. In the nervous system, it is secreted by the notochord, ventralizes the neural tube, inducing the floor plate and motor neurons. In the Limb it is secreted by the zone of polarizing activity (ZPA) organizing limb axis formation.

'''Tbx -''' T-box genes (transcription factor) involved in mouse forelimb (Tbx4) and hindlimb (Tbx5) specification.

'''transcription factor-''' a factor (protein or protein with steroid) that binds to DNA to alter gene expression, usually to activate. (eg steroid hormone+receptor, Retinoic acid+Receptor, Hox, Pax, Lim, Nkx-2.2).

'''vertebral body-''' formed by centrum, vertebral arch, facets for ribs. It is the mature vertebral structure formed by the 5 secondary ossification centers after puberty.

'''vertebral column -''' name given to the complete structure formed from the alternating segments of vertebra and intervertebral discs which support the spinal cord.

'''vertebral foramen -''' the dorsal cavity within each vertebra, generated by the vertebral arch that surrounds the spinal cord.

'''Wnt7a -''' The designation 'Wnt' was derived from 'wingless' and 'int'. The Wnt gene was first defined as a protooncogene, int1. Humans have at least 4 Wnt genes: Wnt7a gene is at 3p25 encoding a 349aa secreted glycoprotein. A patterning switch with different roles in different tissues. The mechanism of Wnt distribution (free diffusion, restricted diffusion and active transport) and all its possible cell receptors are still being determined. At least one WNT receptor is Frizzled (FZD). The Frizzled gene family encodes a seven-transmembrane receptor.

==Images==
<gallery>
File:Bone remodeling cycle.jpg|Bone remodeling cycle
</gallery>

{{Glossary}}
{{Footer}}

Lecture - Neural Crest Development

2013-09-04T04:28:52Z

Z3283213:

== Introduction ==
[[File:Stage11 sem21.jpg|thumb|300px|Human embryo neural crest cells ([[Week 4]], [[Carnegie stage 11|stage 11]])]]
The neural crest are bilaterally paired strips of cells arising in the ectoderm at the margins of the neural tube. These cells migrate to many different locations and differentiate into many cell types within the embryo. This means that many different systems (neural, skin, teeth, head, face, heart, endocrine, gastrointestinal tract) will also have a contribution fron the neural crest cells.

In the body region, neural crest cells also contribute the peripheral nervous system (both neurons and glia) consisting of sensory ganglia (dorsal root ganglia), sympathetic and parasympathetic ganglia and neural plexuses within specific tissues/organs.

In the head region, neural crest cells migrate into the pharyngeal arches (as shown in movie below) forming '''ectomesenchyme''' contributing tissues which in the body region are typically derived from mesoderm (cartilage, bone, and connective tissue). General neural development is also covered in Neural Notes.

==Lecture Plan==
[[File:Carnegie stage 13 caudal trunk.jpg|thumb|Human Embryo (Carnegie stage 13) caudal trunk<ref><pubmed>18689800</pubmed>| [http://hmg.oxfordjournals.org/cgi/content/full/17/21/3411 Hum Mol Genet.]</ref>]]

* What is the neural crest?
* Where does neural crest come from?
* Derivatives of the neural crest
* Migration of different types of neural crest
* Molecular biology of neural crest
* Congenital anomalies due to defects in neural crest migration

'''Lecture Date: 2013-09-10 Lecture Time: 16:00 Venue: BioMed E; Speaker: Professor Ken Ashwell'''

'''The Powerpoint file used to present this lecture is available as a pdf document [[Media:NeuralCrest.pdf‎‎| HERE]]'''

'''A recording of the lecture will be available afterwards at the Echo Centre accessible via Blackboard.'''

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00017-5&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00017-5 Chapter 17 – Nervous System]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00009-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00009-6 Chapter 9 – Pharyngeal Apparatus, Face, and Neck]

|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10010-7 Chapter 10 - Development of the Peripheral Nervous System]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10016-8 Chapter 16 - Development of the Pharyngeal Apparatus and Face]
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Neural Crest Links}}
|}

==Neural Crest Migration in the Head==
{| border='0px'
|-
| <Flowplayer width="408" height="320" autoplay="true">Chicken-neural crest migration 01.flv</Flowplayer>
| valign="top" |[[File:Chicken-neural-crest-migration-01.jpg|300px]]
Chicken embryo sequence shows the migration of DiI-labeled neural crest cells towards the branchial arches as the embryo.
White rings indicate migration of individual cells. Each image represents 10 confocal sections separated by 10 microns.

|-
|}

Movie Source: Original Neural Crest movies kindly provided by Paul Kulesa.

'''Related Movies:''' [[Movie - Chicken Neural Crest Migration 01|Migration 01]] | [[Movie - Chicken Neural Crest Migration 02|Migration 02]] | [[Movie - Chicken Neural Crest Migration 03|Migration 03]] | [[Movie - Chicken Neural Crest Migration 04|Migration 04]] | [[Movie - Chicken Neural Crest Migration 05|Migration 05]] | [[Movie - Chicken Neural Crest Migration 06|Migration 06]] | [[Movie - Chicken Neural Crest Migration 07|Migration 07]]

==Early Development and Neural Derivatives==
[[File:Neuralplate cartoon.png|right]]
* bilaminar embryo- hypoblast
* trilaminar embryo - ectoderm layer
** neural plate - neural groove - neural tube and neural crest
* cranial expansion of neural tube - central nervous system
* caudal remainder of neural tube - spinal cord

Neural Crest - contributes both neural and non-neural cells
* dorsal root ganglia
* parasympathetic / sympathetic ganglia.

==Neural Crest Origin==
* lateral region of neural plate
* dorsal neural fold->tube

Two main embryo regions
* '''Head''' (CNS level) - differentiate slightly earlier, mesencephalic region of neural folds.
* '''Body''' (spinal cord level) - lateral edges of fused neural tube.

== Neural Crest Generation ==

* cranial region - Begins when still neural fold
* spinal cord - from day 22 until day 26
** after closure of caudal neuropore
** rostro-caudal gradient of differentiation

Studies using the chicken model demonstrated that they are not a segregated population. Interactions between the neural plate and epidermis can generate neural crest cells, since juxtaposition of these tissues at early stages results in the formation of neural crest cells at the interface.

At cranial levels, neuroepithelial cells can regulate to generate neural crest cells when the endogenous neural folds are removed, probably via interaction of the remaining neural tube with the epidermis.

Progenitor cells in the neural folds are multipotent, having the ability to form multiple ectodermal derivatives, including epidermal, neural crest, and neural tube cells the neural crest is an induced population that arises by interactions between the neural plate and the epidermis.

The competence of the neural plate to respond to inductive interactions changes as a function of embryonic age.

(Text from: Bronner-Fraser M PNAS 1996 Sep 3;93(18):9352-7)

== Neural Crest Derivatives ==
Neural crest progenitor cells migrate throughout the embryo and give rise to many different adult cells.

This Includes: ganglia cranial, dorsal root, sympathetic trunk, celiac, renal, plexus in GIT, glia, schwann cells, melanocytes (skin), and adrenal medulla (chromaffin cells).

In the head region neural crest also gives rise to a number of connective tissue structures.

==Neural Crest - Head==
See also [[Lecture - Head Development]]
[[File:Mouse_eye_TGF-beta_model.jpg|thumb|Eye Development]]
[[File:Mouse-E10.5 ganglia Sox10.jpg|thumb|Mouse E10.5- neural crest cell distribution (black)]]

Mesencephalon and caudal Proencephalon

* parasympathetic ganglia CN III
* connective tissue around eye and nerve
* head mesenchyme
* neural connective tissue (meninges)

Mesencephalon and Rhombencephalon

* pharayngeal arches
** look at practical notes on neck and head.
* cartilage rudiments (nose, face, middle ear)
* face and facial skeleton
* dermis, smooth muscle and fat
* odontoblasts of developing teeth

Rhombencephalon

* C cells of thyroid
* cranial nerve ganglia
* neurons and glia
* parasympathetic of VII, IX, X
* sensory ganglia of V, VII, VIII, IX, X

==Neural Crest - Peripheral Nervous System==

* peripheral nervous system
* dorsal root ganglia (sensory N)
* parasympathetic ganglia
* sympathetic ganglia
* motoneurons in both ganglia
* all associated glia

== Neural Crest Migration ==
===Head===
[[File:Hindbrain neural crest migration.jpg|thumb|Hindbrain neural crest migration]]
{| border='0px'
|+ '''Neural crest migration in the head in chicken''' ([[Movies_-_Chicken_Neural_Crest|chicken neural crest movies overview]])
|-
| [[File:Chicken-neural-crest-migration-01.jpg|90px|link=Movie - Chicken Neural Crest Migration 01]]
| [[File:Chicken-neural-crest-migration-02.jpg|90px|link=Movie - Chicken Neural Crest Migration 02]]
| [[File:Chicken-neural-crest-migration-03.jpg|90px|link=Movie - Chicken Neural Crest Migration 03]]
| [[File:Chicken-neural-crest-migration-04.jpg|90px|link=Movie - Chicken Neural Crest Migration 04]]
| [[File:Chicken-neural-crest-migration-05.jpg|90px|link=Movie - Chicken Neural Crest Migration 05]]
| [[File:Chicken-neural-crest-migration-06.jpg|90px|link=Movie - Chicken Neural Crest Migration 06]]
| [[File:Chicken-neural-crest-migration-07.jpg|90px|link=Movie - Chicken Neural Crest Migration 07]]
|}

[[File:Mouse_head_E9-neural_crest_GFP.jpg|300px||Mouse_head_E9-neural_crest_GFP]] [[File:Hindbrain neural crest migration.jpg|300px|Hindbrain neural crest migration]] [[File:Mouse-E9.5-Sox10.jpg|300px|Mouse-E9.5-Sox10.jpg]]
===Trunk===

===Cardiac Outflow Tract===

[[File:Cardiac_Neural_Crest_Migration.jpg|300px]]

[[File:Human neural crest cell migration-in vitro.jpg|thumb|Human neural crest cell migration (in vitro)<ref><pubmed>18689800</pubmed>| [http://hmg.oxfordjournals.org/cgi/content/full/17/21/3411 Hum Mol Genet.]</ref>]]
[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3118 Figure 13.2. Neural crest cell migration in the trunk of the chick embryo]
* Neural crest at the level of the body have two general migration pathways, defined by the position of the somite
** medial pathway - between the neural tube and the somite
** lateral pathway - between the somite and the body wall
[[File:Trunk neural crest migration.jpg|thumb|Trunk neural crest migration]]
* A recent study of guidance of neural crest cells (NCC) in mice show migrate 3 specific pathways.
** SEMA3A and its receptor neuropilin 1 (NRP1) - act as repulsive guidance cues
** migration pathway did not affect specification - differs from the concept of migration pathway specifying the neural crest cell differentiation pathway

Neural crest at the level of the head have a different migration pathway. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3134 Figure 13.7. Cranial neural crest cell migration in the mammalian head]

===Sympathetic Ganglia and Adrenal Medulla===
[[File:Adrenal_medulla.jpg|300px]]

[[Media:Adrenal_medulla.mov]]

===Enteric nervous system===

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A63004&rendertype=figure&id=A63009 Figure 1. Diagram of an E10 embryo showing the origins of neural crest cells that colonize the developing gastrointestinal tract]

==Historic Migration Experiments==
Key early experiments in understanding the pattern of neural crest migration were carried out by [[Embryology_History_-_Nicole_Le_Douarin|LeDouarin]] in the 1980's (see Development of the peripheral Nervous system from the neural crest, Ann Rev Cell Biol 4 p375)
[http://www.sdbonline.org/archive/dbcinema/ledouarin/ledouarin.html Quail-Chick Chimeras] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.63 Figure 1.11. Neural crest cell migration Chimera experiment]

These transplantation studies in chicken/quail chimeras utilised the different nucleoli appearance of cells to differentiate different species. Thus transplanation and subsequent histological processing allowed identification of the migration path and final destination of transplanted neural crest cells.

Similar later experiments have now been carried out using the neural crest cells molecularly tagged with (LacZ).

==Abnormalities==

===Neuroblastoma===
[[File:Neuroblastoma.jpg|thumb|Neuroblastoma]]
[[File:Childhood cancer survival rates.jpg|thumb|Childhood cancer survival rates]]

[http://www.ncbi.nlm.nih.gov/omim/256700 OMIM - Neuroblastoma]

===Digeorge Syndrome (DGS)===
[[File:Digeorge chromosome22.jpg|thumb|Digeorge chromosome 22]]
* DiGeorge syndrome is the most frequent microdeletion syndrome in humans caused by a hemizygous deletion (1.5 to 3.0-Mb) of chromosome 22q11.2.
* Velo-cardio-facial syndrome, Hypoplasia of thymus and parathyroids, third and fourth pharyngeal pouch syndrome.
* Abnormalities: cardiovascular, thymic and parathyroid, craniofacial anomalies, renal anomalies, hypocalcemia and immunodeficiency.

===Intestinal Aganglionosis===
[[File:Megacolon surgery.gif]]
[[File:Megacolon stoma.gif]]
* Intestinal Aganglionosis, Hirschsprung's Disease or Megacolon
* lack of enteric nervous system (neural ganglia) in the intestinal tract responsible for gastric motility (peristalsis).
* severity is dependent upon the amount of the GIT that lacks intrinsic ganglia, due to developmental lack of neural crest migration into those segments.
* first indication in newborns is an absence of the first bowel movement, other symptoms include throwing up and intestinal infections.
* Clinically this is detected by one or more tests (barium enema and x ray, manometry or biopsy) and can currently only be treated by surgery. A temoporary ostomy (Colostomy or Ileostomy) with a stoma is carried out prior to a more permanent pull-through surgery.

===Melanoma===
[[File:Melanoma.jpg]]
* In Australia each year 8,800 people are diagnosed with melanoma, and almost 1000 people die (Data, Cancer Council Australia).
* Two different findings on the reprogramming of melanoma cells, which have a neural crest origin, when transplanted between species into embryos.

[http://www.melanoma.com/staging.html Melanoma staging]

===Neurofibromatosis Type 1 (NF1)===

* Neurofibromatosis Type 1 (von Recklinghausen) occurs in 1 in 3,000 to 4,000 people with characteristic skin blemishes forming in early childhood.
* Multiple ''café-au-lait'' spots (flat skin patches darker than the surrounding area) appear in early childhood which increase in both size and number with age.
* tumors can develop along nerves in the skin, brain, and other parts of the body. In the iris of the eye, Lisch nodules (benign growths) also appear
:(French, ''café-au-lait'' = coffee with milk)

[http://atlasgeneticsoncology.org/Tumors/NeurofibromaID5098.html Atlas of Genetics and Cytogenetics in Oncology- Neurofibroma]

===Tetralogy of Fallot===
Cardiac abnormality possibly stemming from abnormal [[N#neural crest|neural crest]] migration. Named after Etienne-Louis Arthur Fallot (1888) who described it as "''la maladie blue''". (More? [[Cardiovascular System Development]] | [[Cardiac_Embryology|Cardiac Tutorial]] | [[2009_Lecture_21|Lecture - Heart]] | [[Cardiovascular System - Abnormalities]])

===Treacher Collins syndrome===

(TCS) A genetic developmental abnormality results from autosomal dominant mutations of the gene TCOF1 encoding the protein Treacle, identified in [http://www.ncbi.nlm.nih.gov/pubmed/8563749 2006]. The syndrome is characterized by hypoplasia of the facial bones, cleft palate, and middle and external ear defects. These defects may relate to the effects on neural crest migration. (More? [[Neural Crest Development]] | [http://www.ncbi.nlm.nih.gov/omim/606847 OMIM - TCOF1] | [http://www.ncbi.nlm.nih.gov/pubmed/8563749 PMID: 8563749])

== References ==
<references/>
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter Chapter 10 The Pharyngeal Apparatus pp201 - 240.
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 12 Development of the Head, the Neck, the Eyes, and the Ears pp349 - 418.

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3109#3133 The Cranial Neural Crest] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3111 Figure 13.1. Regions of the neural crest] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3134 Figure 13.7. Cranial neural crest cell migration in the mammalian head] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3118 Figure 13.2. Neural crest cell migration in the trunk of the chick embryo] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3138 Figure 13.10. Separation of the truncus arteriosus into the pulmonary artery and aorta] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.5460 Figure 22.23. Chick embryo rhombomere neural crest cells and their musculoskeletal packets] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3127 Figure 13.4. Segmental restriction of neural crest cells and motor neurons by the ephrin proteins of the sclerotome] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.43 Figure 1.3. Pharyngeal arches] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.table.3135 Table 13.2. Some derivatives of the pharyngeal arches]

:Neural Crest Experiments: [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.63 Figure 1.11. Neural crest cell migration Chimera experiment] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3130 Figure 13.5. Pluripotency of trunk neural crest cells]

* '''Molecular Biology of the Cell''' Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=mboc4.figgrp.3946 Figure 21-80. The main pathways of neural crest cell migration] [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=mboc4.figgrp.3968 Figure 21-91. Diagram of a 2-day chick embryo, showing the origins of the nervous system] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=neural_crest&rid=mboc4.figgrp.3511 Figure 19-23. An example of a more complex mechanism by which cells assemble to form a tissue]

* '''Neuroscience''' Purves, Dale; Augustine, George J.; Fitzpatrick, David; Katz, Lawrence C.; LaMantia, Anthony-Samuel; McNamara, James O.; Williams, S. Mark. Sunderland (MA): Sinauer Associates, Inc.; c2001[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=neurosci.figgrp.1449 Figure 22.1. Neurulation in the mammalian embryo] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=neurosci.figgrp.1503 Figure 22.12. Cell signaling during the migration of neural crest cells]
* '''Madame Curie Bioscience Database''' Chapters taken from the Madame Curie Bioscience Database (formerly, Eurekah Bioscience Database) [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A53006 Cranial Neural Crest and Development of the Head Skeleton] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=ch2957 Neural Crest Cells and the Community of Plan for Craniofacial Development: Historical Debates and Current Perspectives] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A63004&rendertype=figure&id=A63009 Figure 1. Diagram of an E10 embryo showing the origins of neural crest cells that colonize the developing gastrointestinal tract]

* '''Basic Neurochemistry: Molecular, Cellular, and Medical Aspects''' Siegel, George J.; Agranoff, Bernard W.; Albers, R. Wayne; Fisher, Stephen K.; Uhler, Michael D., editors Philadelphia: Lippincott,Williams & Wilkins; c1999[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=bnchm.figgrp.1881 Figure 27-10. Neuropoietic model of neural crest cell lineage] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=neural_crest&rid=bnchm.figgrp.1883 Figure 27-11. Growth factor control of neural crest lineage decisions] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=neural_crest&rid=bnchm.figgrp.1893 Figure 27-15. The Schwann cell lineage]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=neural_crest neural crest]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=neural_crest neural crest]

== External Links ==
{{External Links}}

* University of Michigan [http://www.biology.lsa.umich.edu/research/labs/ktosney/file/Res/ResNc.html Tosney Lab]
* Stowers Institute [http://www.stowers-institute.org/labs/KulesaLab.asp Kulesa Lab] | [http://www.stowers-institute.org/labs/TrainorLab.asp Trainor Lab]
* University College London [http://www.anat.ucl.ac.uk/research/mayor/index.html Mayor Lab]
* University of Iowa [http://www.anatomy.uiowa.edu/pages/directory/faculty/cornell.asp Cornell Lab]
* Washington University in St. Louis, School of Medicine, Department of Pediatrics [http://peds.wustl.edu/research/labs/Heuckeroth_Robert_O/ Heuckeroth Lab]

{{Glossary}}
{{Footer}}
[[Category:Neural Crest]]

==Reference==
<pubmed>10683170</pubmed>

[[Category:Neural Crest]]

Lecture - Head Development

2013-09-04T04:24:33Z

Z3283213:

= Head Development=
[[File:Stage14_sem2cl.jpg|right]]
== Introduction ==

[[File:Stage16-18 face.jpg|thumb|Human face development (Week 6 to 7)]]
The face is the anatomical feature which is truly unique to each human, though the basis of its general development is identical for all humans and similar to that seem for other species. The face has a complex origin arising from a number of head structures and sensitive to a number of teratogens during critical periods of its development. The related structures of upper lip and palate significantly contribute to the majority of face abnormalities.

The head and neck structures are more than just the face, and are derived from pharyngeal arches 1 - 6 with the face forming from arch 1 and 2 and the frontonasal prominence. Each arch contains similar Arch components derived from endoderm, mesoderm, neural crest and ectoderm. These components though will form different structures depending on their arch origin. Because the head contains many different structures also review notes on [[Sensory System Development|Special Senses]]), [[Respiratory System Development|Respiratory]], Integumentary (Teeth), [[Endocrine System Development|Endocrine]] (thyroid, parathyroid, pituitary, thymus) and [[Ultrasound]]- Cleft lip/palate.

==Lecture Plan==
* Origins of the head and neck tissues
* Pharyngeal arches
* Development of the face
* Development of the palate
* Development of the tongue and pharynx
* Derivatives of the pharyngeal arches and pouches
* Development of the skull

'''Lecture Date: 2013-09-10 Lecture Time: 12:00 Venue: Wallace Wurth LG03; Speaker: Professor Ken Ashwell'''

'''The Powerpoint file used to present this lecture is available as a pdf document [[Media:HeadDevelopment.pdf‎‎| HERE]]'''

'''A recording of the lecture will be available on Lectopia
[https://secured.learningandteaching.unsw.edu.au/lectopia/lectopiaLogin/default.cfm?ut=153 - Lectopia Login page]'''

[[File:Pharyngeal arch structure cartoon.gif]][[File:Stage13 pharyngeal arch excerpts.gif|300px]]

==Textbooks==
[[File:Pharyngeal_arch_cartilages.jpg|thumb]]
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00009-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00009-6 Chapter 9 – Pharyngeal Apparatus, Face, and Neck]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00018-7&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00018-7 Chapter 18 – Development of Eyes and Ears]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10016-8 Chapter 16 - Development of the Pharyngeal Apparatus and Face]

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10017-X Chapter 17 - Development of the Ears and Eyes]
|}

===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Head Links}}
|}

* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter Chapter 10 The Pharyngeal Apparatus pp201 - 240.
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 12 Development of the Head, the Neck, the Eyes, and the Ears pp349 - 418.

==Movies==

{| border='0px'
|-
| [[File:Stage16-18_face_01_icon.jpg|120px|link=Movie_-_Stage_16_to_18_Face]]
| [[File:Stage15-22 head 01 icon.jpg|120px|link=Movie_-_Stage_15_to_22_Head]]
| [[File:Face 001 icon.jpg|120px|link=Development_Animation_-_Face]]
| [[File:Palate_001 icon.jpg|120px|link=Development_Animation_-_Palate 1]]
| [[File:Palate_002 icon.jpg|120px|link=Development_Animation_-_Palate 2]]
| [[File:Tongue_001 icon.jpg|120px|link=Development_Animation_-_Tongue]]
|-
| [[Movie_-_Stage_16_to_18_Face|Face]]

Stage 16 to 18
| [[Movie_-_Stage_15_to_22_Head|Head]]

Stage 15 to 22
| [[Development_Animation_-_Face|Face]]
| [[Development_Animation_-_Palate 1|Palate 1]]
| [[Development_Animation_-_Palate 2|Palate 2]]
| [[Development_Animation_-_Tongue|Tongue]]
|-
|}

==Animation of Face Development==
{|
| <Flowplayer width="420" height="500" autoplay="true">Face_001.flv</Flowplayer>

[[Media:Face_001.mov|Quicktime version]]
|
'''Development of the Face'''

This animation shows a ventral view of development of the human face from approximately week 5 through to neonate.

The separate embryonic components that contribute to the face have been colour coded.

* '''Frontonasal Prominence (white)'''
* '''Frontonasal Prominence - Lateral nasal''' (purple)
* '''Frontonasal Prominence - Medial nasal''' (green)
* '''Pharyngeal Arch 1 - Maxillary prominence''' (yellow)
* '''Pharyngeal Arch 1 - Mandibular prominence''' (orange)
* '''Stomodeum (black)'''

The [[S#stomodeum|stomodeum]] is the primordial mouth region and a surface central depression lying between the forebrain bulge and the heart bulge. At the floor of the stomodeum indentation is the [[B#buccopharyngeal membrane|buccopharyngeal membrane]] (oral membrane).

Note the complex origin of the maxillary region (upper jaw) requiring the fusion of several embryonic elements, abnormalities of this process lead to [[C#cleft lip|cleft lip]] and [[C#cleft palate|cleft palate]].

See also the movie ([[Quicktime_Movie_-_Stage_16_to_18_Face|Quicktime]] | [[Quicktime_Movie_-_Stage_16_to_18_Face|Flash]]) showing a similar view of human embryo faces between [[Carnegie stage 16|Carnegie stage 16]] to [[Carnegie stage 18|18]].

'''Links:''' [[Quicktime Development Animation - Face]] | [[Media:Face_001.mov|Quicktime version]] | [[Head Development]]
|}

==Buccopharyngeal Membrane==

These images of the Stage 11 embryo show the breakdown of the buccopharyngeal membrane.
<gallery>
File:Stage11 sem4c.jpg|Low power ventral view of the Buccopharyngeal Membrane
File:Stage11 sem3c.jpg|Higher power ventrolateral view of the Buccopharyngeal Membrane
File:Stage11 sem2c.jpg|Close up view of the degenerating Buccopharyngeal Membrane
</gallery>

==The Pharynx==
[[File:Head arches cartoon.jpg|300px]]
[[File:Stage13 B2 excerpt.gif]]
[[File:Pharynx cartoon.jpg|300px]]

The cavity within the pharyngeal arches forms the pharynx.

* begins at the buccopharyngeal membrane (oral membrane), apposition of ectoderm with endoderm (no mesoderm between)
* expands behind pharyngeal arches
* narrows at glottis and bifurcation of gastrointestinal (oesophagus) and respiratory (trachea) systems
* regions on roof, walls and floor have important contributions to endocrine in oral and neck regions
* also contributes to tongue development

== Pharyngeal Arch Components ==
[[File:Pharyngeal arch structure cartoon.gif]]

Major features to identify for each: '''arch''', '''pouch''', '''groove''' and '''membrane'''. Contribute to the formation of head and neck and in the human appear at the 4th week. The first arch contributes the majority of upper and lower jaw structures.

==Pharyngeal Arch Development==

* '''branchial arch''' (Greek. ''branchia'' = gill)
* arch consists of all 3 trilaminar embryo layers:
# '''ectoderm''' - outside embryo surface (and neural crest in core)
# '''mesoderm''' - core of mesenchyme
# '''endoderm''' - inside pharynx

===Neural Crest ===
[[File:Head arches cartoon.jpg|thumb|neural crest migration]]
* Mesenchyme invaded by neural crest generating connective tissue components
* cartilage, bone, ligaments
* arises from midbrain and hindbrain region

===Arch Features===

Each arch contains: '''artery, cartilage, nerve and muscular''' component

Arches and Phanynx Form the face, tongue, lips, jaws, palate, pharynx and neck cranial nerves, sense organ components, glands

* Humans have 5 arches - 1, 2, 3, 4, 6 (Arch 5 does not form or regresses rapidly)
* from in rostro-caudal sequence, Arch 1 to 6 from week 4 onwards
* arch 1 and 2 appear at time of closure of cranial neuropore

* Face - mainly arch 1 and 2
* Neck components - arch 3 and 4 (arch 4 and 6 fuse)

{|
|
* arch
* groove
** externally separates each arch
*** also called a cleft
** only first pair persist as external auditory meatus
* pouch
** internally separates each arch
** pockets from the pharynx
* membrane
** ectoderm and endoderm contact regions
** only first pair persist as tympanic membrane
| [[File:Stage13_B2_excerpt.gif]]
|}

Pharyngeal Arch 1 (Mandibular Arch) has 2 prominences
* smaller upper- maxillary forms maxilla, zygomatic bone and squamous part of temporal
* larger lower- mandibular, forms mandible

Pharyngeal Arch 2 (Hyoid Arch)
* forms most of hyoid bone

Pharyngeal Arch 3 and 4
* neck structures

==Arch Arteries==
Blood Pathway: placental vein -> liver -> heart -> truncus arteriosus -> aortic sac -> '''arch arteries''' -> dorsal aorta -> placental artery

* Arch 1 - mainly lost, form part of '''maxillary artery'''
* Arch 2 - regresses to small '''stapedial arteries'''
* Arch 3 - '''common carotid arteries, internal carotid arteries'''
* Arch 4 - left forms part of '''aortic arch''', right forms part '''right subclavian artery'''
* Arch 6 - left forms part of '''left pulmonary artery''', right forms part of '''right pulmonary artery'''

==Arch Cartilage==
[[File:Meckel.jpg|thumb|Meckel's cartilage, first pharyngeal arch]]
[[File:Pharyngeal_arch_cartilages.jpg|thumb|Pharyngeal arch cartilages]]
* Arch 1 - Meckel's cartilage, horseshoe shaped
** dorsal ends form malleus and incus
** midpart forms ligaments (ant. malleus, sphenomandibular)
** ventral part forms mandible template
<gallery>
File:Gray0178.jpg|Embryo CRL 24 mm outer aspect (week 8)
File:Gray0178.jpg|Embryo CRL 24 mm inner aspect
File:Gray0180.jpg|Fetus CRL 95 mm outer aspect (week 13-14)
File:Gray0181.jpg|Fetus CRL 95 mm inner aspect
</gallery>
* Arch 2 - Reichert's cartilage
** dorsal ends form '''stapes''' and '''temporal bone styloid process'''
** ventral part ossifies to form '''hyoid bone''' components (lesser cornu and superior body)

* Arch 3 - forms '''greater cornu''' and '''inferior part of hyoid'''

* Arch 4&6 - form '''laryngeal cartilages''', except epiglottis (from hypobranchial eminence)

==Arch Muscle==
* Arch 1 - '''muscles of mastication''', mylohyoid, tensor tympanic, anterior belly digastric
* Arch 2 - '''muscles of facial expression''', stapedius, stylohyoid, posterior belly digastric
* Arch 3 - stylopharyngeus
* Arch 4&6 - crycothyroid, pharynx constrictors, larynx muscles, oesophagus (st. muscle)

==Arch Nerve==
* Arch 1 - '''CN V''' trigeminal, caudal 2/3 maxillary and mandibular, cranial 1/3 sensory nerve of head and neck, mastication motor
* Arch 2 - '''CN VII''' facial
* Arch 3 - '''CN IX''' glossopharyngeal
* Arch 4&6 - '''CN X''' vagus, arch 4 - superior laryngeal, arch 6 - recurrent laryngeal

==Arch Pouches==
{|
|
* Arch 1 - elongates to form '''tubotympanic recess''', tympanic cavity, mastoid antrum, eustachian tube
* Arch 2 - forms tonsillar sinus, mostly oblierated by palatine tonsil
* Arch 3 - forms '''inferior parathyroid''' and '''thymus'''
* Arch 4 - forms '''superior parathyroid''', '''parafollicular cells of thyroid'''
| [[File:Pharyngeal_pouches.jpg]]
|}

==Thyroid Gland ==
[[File:Stage13 and 22 thyroid development.jpg|thumb|Stage13 and 22 thyroid development]]
* not a pouch structure
* first endocrine organ to develop day 24
* from '''floor of pharynx'''
* descends thyroglossal duct (which closes)
* upper end at foramen cecum

==Anterior Pituitary==
[[File:Historic-pituitary.jpg|thumb|Pituitary]]
* not a pouch structure
* boundary epitheilal '''ectoderm''' in the roof of the pharynx
* forms a pocket (Rathke's pouch) that comes into contact with the ectoderm of developing brain.
** Rathke's pouch is named after German embryologist and anatomist Martin Heinrich Rathke (1793 - 1860).

==Face Development==
[[File:Stage16-18 face animation.gif|right]]
Begins week 4 centered around stomodeum, external depression at oral membrane

5 initial primordia from neural crest mesenchyme
* single frontonasal prominence (FNP) - forms forehead, nose dorsum and apex
* nasal placodes develop later bilateral, pushed medially
* paired maxillary prominences - form upper cheek and upper lip
* paired mandibular prominences - lower cheek, chin and lower lip

[[:File:Face animation.gif]]

==Head/Skull==

* '''chondrocranium''' forms base of skull
** in lower vertebrates encases brain
* '''cranial vault'''
** calveria
* '''facial skeleton'''
** pharyngeal arches

==Sensory Placodes ==
'''MH -''' will cover sensory placodes in Senses Lecture.

* During week 4 a series of thickened surface ectodermal patches form in pairs rostro-caudally in the head region.
** Recent research suggests that all sensory placodes may arise from common panplacodal primordium origin around the neural plate, and then differentiate to eventually have different developmental fates.
* These sensory placodes will later contribute key components of each of our special senses (vision, hearing and smell).
* Other species have a number of additional placodes which form other sensory structures (fish, lateral line receptor).
* Note that their initial postion on the developing head is significantly different to their final position in the future sensory system

===Otic placode===
* in the stage 13/14 embryo (shown below) the otic placode has sunk from the surface ectoderm to form a hollow epithelial ball, the otocyst, which now lies beneath the surface surrounded by mesenchyme (mesoderm). The epithelia of this ball varies in thickness and has begun to distort, it will eventually form the inner ear membranous labyrinth.

{|
| [[File:Stage12_sem6.jpg|400px]]

Stage 12 Embryo - otic placode
| [[File:Stage13_otocyst.jpg|400px]]

Stage 13 Embryo - otocyst
|}

===Lens placode===
[[File:Stage14_sem2l.jpg|thumb|Stage 14 Embryo - - optic and nasal placodes]]
lies on the surface, adjacent to the outpocketing of the nervous system (which will for the retina) and will form the lens.

===Nasal placode===
has 2 components (medial and lateral) and will form the nose olefactory epithelium.

==Head Growth==
[[File:Fetal_head_lateral.jpg|thumb|Fetal Head (12 weeks) showing bone and cartilage]]
* continues postnatally - fontanelle allow head distortion on birth and early growth
* bone plates remain unfused to allow growth, puberty growth of face

===Skull Overview===
[[File:Keibel_Mall_321.jpg|thumb|Lateral view of the cranium of a human fetus 80 mm long.]]
'''Chondrocranium''' - formed from paraxial mesoderm
* cranial end of vertebral column
* modified vertebral elements
* occipital and cervical sclerotome
* bone preformed in cartilage (endochondrial ossification)

'''Cranial Vault and Facial Skeleton''' - formed from neural crest
* muscle is paraxial mesoderm
* somitomeres and occipital somites

Calveria - bone has no cartilage (direct ossification of mesenchyme)
* bones do not fuse, fibrous sutures 1. allow distortion to pass through birth canal 2. allow growth of the brain
* 6 fontanelles, posterior closes at 3 months, anterior closes at 18 months
{| class="prettytable"
| [[File:Skull anterior.gif]]
| [[File:Skull_superior.gif]]
| [[File:Skull lateral view.gif]]

|-
| anterior view
| superior view
| lateral view

|-
| showing anterior fontenelle, sutures, mandible
| showing anterior fontenelle, sutures
| showing suture, mandible

|}

==Palate==
The palate has two key stages of development during embryonic and an early fetal involving the fusion of structures (epithelia to mesenchymal).

=== Embryonic===
Primary palate, fusion in the human embryo between stage 17 and 18, from an epithelial seam to the mesenchymal bridge.

[[File:Stage17-18 Primary palate.gif]]

===Fetal===
[[File:Stage_22_image_061.jpg|thumb]]
Secondary palate, fusion in the human embryo in week 9. This requires the early palatal shelves growth, elevation and fusion during the early embryonic period. The fusion event is to both each other and the primary palate. [[:File:Palatal shelves animation.gif|palatal shelf elevation]] | [[:File:palate.gif|secondary palate]]

==Ear Auricles==

* form from 6 hillocks (week 5)
* 3 on each of arch 1 and 2

==Tongue Development==
[[File:Tongue1.png|200px]] [[File:Tongue2.png|200px]] [[File:Tongue3.png|200px]]

* '''Ectoderm''' of the first arch surrounding the stomodeum forms the epithelium lining the buccal cavity.
** Also the salivary glands, enamel of the teeth, epithelium of the body of the tongue.
* Tongue develops "inside" the floor of the oral cavity
** it is not readily visible in the external views of the embryonic (Carnegie) stages of development.

* Contributions from all arches, which changes with time
* begins as swelling rostral to foramen cecum, '''median tongue bud'''

** Arch 1 - oral part of tongue (ant 3/2)
** Arch 2 - initial contribution to surface is lost
** Arch 3 - pharyngeal part of tongue (post 1/3)
** Arch 4 - epiglottis and adjacent regions

[[:File:tongue.gif|tongue development animation]]

===Tongue muscle===
[[File:Tongue-muscle.jpg|thumb|tongue muscle]]
* Tongue muscles originate from the somites. Tongue muscles develop before masticatory muscles and is completed by birth.
* Masticatory muscles originate from the somitomeres. These muscles develop late and are not complete even at birth.

===Salivary Glands===

* epithelial buds in oral cavity (wk 6-7) extend into mesenchyme
* parotid, submandibular, sublingual

== Abnormalities ==
===Cleft Lip and Palate===
* 300+ different abnormalities, different cleft forms and extent, upper lip and ant. maxilla, hard and soft palate

====Cleft Palate====
* Cleft palate has the International Classification of Diseases code 749.0.
* In Australia the national rate (1982-1992) for this abnormalitity in births was 4.8 - 6/10,000 births, which represented 1,530 infants 5.5% were stillborn and 11.5% liveborn died during neonatal period and slightly more common in twin births than singleton.

====Cleft Lip====
* The International Classification of Diseases code 749.1 for isolated cleft lip and 749.2 for cleft lip with cleft palate.
* In Australia the national rate (1982-1992) for this abnormalitity was 8.1 - 9.9 /10,000 births. Of 2,465 infants 6.2% were stillborn and 7.8% liveborn died during neonatal period and the rate was similar in singleton and twin births.

===First Arch Syndrome ===
* There are 2 major types of associated first arch syndromes, Treacher Collins (Mandibulofacial dysostosis) and Pierre Robin (Pierre Robin complex or sequence), both result in extensive facial abnormalites.

==== Treacher Collins Syndrome====

====Pierre Robin Syndrome ====
* Hypoplasia of the mandible, cleft palate, eye and ear defects.
* Initial defect is small mandible (micrognathia) resulting in posterior displacement of tongue and a bilateral cleft palate.

===DiGeorge Syndrome===
* absence of thymus and parathyroid glands, 3rd and 4th pouch do not form
* disturbance of cervical neural crest migration

===Cysts===
* Many different types

=== Facial Clefts===
** extremely rare
* Holoprosencephaly
** shh abnormality

===Maternal Effects ===
* Retinoic Acid - present in skin ointments
*1988 associated with facial developmental abnormalities

===Fetal Alcohol Syndrome===
[[File:FASface.jpg|left]]
Due to alcohol in early development (week 3+) leading to both facial and neurological abnormalities
* lowered ears, small face, mild+ retardation
* Microcephaly - leads to small head circumference
* Short Palpebral fissure - opening of eye
* Epicanthal folds - fold of skin at inside of corner of eye
* Flat midface
* Low nasal bridge
* Indistinct Philtrum - vertical grooves between nose and mouth
* Thin upper lip
* Micrognathia - small jaw

Exposure of embryos in vitro to ethanol simulates premature differentiation of prechondrogenic mesenchyme of the facial primordia (1999)

[http://embryology.med.unsw.edu.au/Defect/page5a.htm Fetal Alcohol Syndrome]

== Table - Structures derived from Arches ==

{| class="prettytable" border=1
| '''Arch'''
| '''Nerve'''
| '''Skeletal Structures'''
| '''Muscles'''
| '''Ligaments'''

|-
| 1 (maxillary/mandibular)
| trigeminal (V)
| mandible, maxilla, malleus, incus
|  
| ant lig of malleus, sphenomandibular ligament

|-
| 2 (hyoid)
| facial (VII)
| stapes, styloid process, lesser cornu of hyoid, upper part of body of hyoid bone
|  
| stylohyoid ligament

|-
| 3
| glossopharyngeal (IX)
| greater cornu of hyoid, lower part of body of hyoid bone
|  
|

|-
| 4 & 6
| superior laryngeal and recurrent laryngeal branch of vagus (X)
| thyroid, cricoid, arytenoid, corniculate and cuneform cartilages
|  
|

|}

=== Structures derived from Arches ===

{| class="prettytable" border=1
| '''Arch'''
| '''Nerve'''
| '''Skeletal Structures'''
| '''Muscles'''
| '''Ligaments'''

|-
| 1 (maxillary/mandibular)
| trigeminal (V)
| mandible, maxilla, malleus, incus
|  
| ant lig of malleus, sphenomandibular ligament

|-
| 2 (hyoid)
| facial (VII)
| stapes, styloid process, lesser cornu of hyoid, upper part of body of hyoid bone
|  
| stylohyoid ligament

|-
| 3
| glossopharyngeal (IX)
| greater cornu of hyoid, lower part of body of hyoid bone
|  
|

|-
| 4 & 6
| superior laryngeal and recurrent laryngeal branch of vagus (X)
| thyroid, cricoid, arytenoid, corniculate and cuneform cartilages
|  
|

|}
'''Skeletal Structures'''

{| class="prettytable" border=1
| [[Image:mandible_sm.jpg]]
| mandible

|-
| [[Image:hyoid_bone_sm.jpg]]
| hyoid

|-
| [[Image:larynx_cartilage_sm.jpg]]
|  

|}

=== Structures derived from Pouches ===
Each pouch is lined with endoderm and generates specific structures.

{| class="prettytable" border=1
| <center>'''POUCH'''</center>
| '''Overall Structure'''
| '''Specific Structures'''

|-
| <center>1</center>
| tubotympanic recess
| tympanic membrane, tympanic cavity, mastoid antrum, auditory tube

|-
| <center>2</center>
| intratonsillar cleft
| crypts of palatine tonsil, lymphatic nodules of palatine tonsil

|-
| <center>3</center>
| inferior parathyroid gland, thymus gland
|

|-
| <center>4</center>
| superior parathyroid gland, ultimobranchial body
|

|-
| <center>5</center>
| becomes part of 4th pouch
|

|}

=== Structures derived from Grooves ===
Only the '''first''' '''groove''' differentiates into an adult structure and forms part of the external acoustic meatus.

=== Structures derived from Membranes ===
At the bottom of each groove lies the membrane which is formed from the contact region of ectodermal groove and endodermal pouch. Only the '''first''' '''membrane''' differentiates into an adult structure and forms the tympanic membrane.

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter Chapter 10 The Pharyngeal Apparatus pp201 - 240.
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 12 Development of the Head, the Neck, the Eyes, and the Ears pp349 - 418.

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.43 Figure 1.3. Pharyngeal arches] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.table.3135 Table 13.2. Some derivatives of the pharyngeal arches] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3109#3133 The Cranial Neural Crest]

* '''Madame Curie Bioscience Database''' Chapters taken from the Madame Curie Bioscience Database (formerly, Eurekah Bioscience Database) [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A53006 Cranial Neural Crest and Development of the Head Skeleton] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=ch2957 Neural Crest Cells and the Community of Plan for Craniofacial Development: Historical Debates and Current Perspectives]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=pharyngeal_arch pharyngeal arch] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=head_development head development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=face_development face development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=pharyngeal_arch pharyngeal arch] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=head_development head development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=face_development face development] |

==Movies==
{| border='0px'
|-
| [[File:Face 001 icon.jpg|90px|link=Development_Animation_-_Face]]
| [[File:Palate_001 icon.jpg|90px|link=Development_Animation_-_Palate 1]]
| [[File:Palate_002 icon.jpg|90px|link=Development_Animation_-_Palate 2]]
| [[File:Tongue_001 icon.jpg|90px|link=Development_Animation_-_Tongue]]
|-
| [[Development_Animation_-_Face|Face]]
| [[Development_Animation_-_Palate 1|Palate 1]]
| [[Development_Animation_-_Palate 2|Palate 2]]
| [[Development_Animation_-_Tongue|Tongue]]
|-
|}

== External Links ==
'''Embryo Images Unit:''' [http://www.med.unc.edu/embryo_images/ Embryo Images Online] | [http://www.med.unc.edu/embryo_images/unit-hednk/hednk_htms/hednktoc.htm Craniofacial Development] | [http://www.med.unc.edu/embryo_images/unit-hednk/hednk_htms/hednk001.htm Cell Populations] | [http://www.med.unc.edu/embryo_images/unit-hednk/hednk_htms/hednk007.htm Pharyngeal Arches] | [http://www.med.unc.edu/embryo_images/unit-hednk/hednk_htms/hednk024.htm Tongue] | [http://www.med.unc.edu/embryo_images/unit-hednk/hednk_htms/hednk026.htm Nose and Upper Lip] | [http://www.med.unc.edu/embryo_images/unit-hednk/hednk_htms/hednk033.htm Palate Development]

'''Research Labs:''' [http://www.weizmann.ac.il/Biological_Regulation/tzahor/research.html tzahor lab]

==Terms==

===palate===

:The roof of the mouth (oral cavity) a structure which separates the oral from the nasal cavity. Develops as two lateral palatal shelves which grow and fuse in the midline. Initally a primary palate forms with fusion of the maxillary processes with the nasal processes in early face formation. Later the secondary palate forms the anterior [[H#hard_palate|hard palate]] which will ossify and separate the oral and nasal cavities. The posterior part of the palate is called the soft palate (velum, muscular palate) and contains no bone. Abnormalities of palatal shelf fusion can lead to [[C#cleft_palate|cleft palate]]. (More? [[Head Development|Head]] | [[Head_Development_-_Abnormalities|Head Abnormalities]] | [http://www.nlm.nih.gov/medlineplus/cleftlipandpalate.html Medline Plus - Cleft Lip and Palate])

===palatogenesis===

:The process of palate formation, divided into primary and secondary palate development. (More? [[Head Development|Head]] | [[Head_Development_-_Abnormalities|Head Abnormalities]] | [http://www.nlm.nih.gov/medlineplus/cleftlipandpalate.html Medline Plus - Cleft Lip and Palate])

===pharyngeal arch===

:([[B#branchial arch|branchial arch]], Greek, ''branchial'' = gill) These are a series of externally visible anterior tissue bands lying under the early brain that give rise to the structures of the head and neck. In humans, five arches form (1,2,3,4 and 6) but only four are externally visible on the [[E#embryo|embryo]]. Each arch has initially identical structures: an internal endodermal pouch, a mesenchymal ([[M#mesoderm|mesoderm]] and [[N#neural crest|neural crest]]) core, a membrane ([[E#endoderm|endoderm]] and [[E#ectoderm|ectoderm]]) and external cleft ([[E#ectoderm|ectoderm]]). Each arch mesenchymal core also contains similar components: blood vessel, nerve, muscular, cartilage. Each arch though initially formed from similar components will differentiate to form different head and neck structures. (More? | [[Head Development]] | [[Endocrine System Development|Endocrine]] | [[Neural Crest Development|Neural Crest]])

===pharyngeal arch artery===

:Each early developing pharyngeal arch contains a lateral pair of arteries arising from the aortic sac, above the heart, and running into the dorsal aorta. later in development these arch arteries are extensively remodelled to form specific components of the vascular system. Pharyngeal Arch 1 arteries are mainly lost and forms part of maxillary artery. Pharyngeal Arch 2 arteries remains to form the stapedial arteries. Pharyngeal Arch 3 arteries forms the common carotid arteries, internal carotid arteries in the neck. Pharyngeal Arch 4 arteries will form part of aortic arch (left arch artery) and part right subclavian artery (right arch artery) Pharyngeal Arch 6 arteries form part of left pulmonary artery (left arch artery) and part of right pulmonary artery (right arch artery). (More? | [[Head Development]] | [[Cardiovascular System Development|Cardiovascular]])

===pharyngeal arch cartilage===

:Each early developing pharyngeal arch contains a horseshoe shaped band of cartilage that acts as a template and contributes to the development of head and neck bony and cartilagenous features, including the middle ear bones. Pharyngeal Arch 1 cartilage (Meckel‚Äôs cartilage) dorsal ends form malleus and incus midpart forms ligaments (ant. malleus, sphenomandibular) ventral part forms mandible template. Pharyngeal Arch 2 cartilage (Reichert‚Äôs cartilage) dorsal ends form stapes and Temporal bone styloid process, ventral part ossifies to form hyoid bone components, lesser cornu and superior body. Pharyngeal Arch 3 cartilage forms hyoid components, greater cornu and inferior part of hyoid. Pharyngeal Arch 4 and 6 cartilage forms laryngeal cartilages except epiglottis (from hypobranchial eminence). (More? [[Head Development]] | [[Hearing_-_Middle_Ear_Development|Middle Ear]])

===pharyngeal arch nerve===

:Each early developing pharyngeal arch contains the developing cranial nerves, as a pair, within the arch mesenchyme. Each cranial nerve is numbered (roman numeral) in rostrocaudal sequence and also has a specific name. The cranial nerve within each arch often relates to the other structures formed from taht arch. Pharyngeal Arch 1 contains the trigeminal nerve (CN V, cranial nerve 5). Pharyngeal Arch 2 contains the facial nerve (CN VII, cranial nerve 7). Pharyngeal Arch 3 contains the glossopharyngeal nerve (CN IX, cranial nerve 9) Pharyngeal Arch 4 and 6 contains the Vagus (CN X cranial nerve 10), forming the adult superior laryngeal and recurrent laryngeal branches. (More? | [[Head Development]] | [[Neural System Development|Neural]] | [[Neural Crest Development|Neural Crest]])

===pharyngeal arch pouch===

:An out-pocketing of the [[E#endoderm|endoderm]] lined pharynx occurring between each developing pharyngeal arch. Each of the pharyngeal arch pouches contributes different components of the head and neck, either cavities or endocrine tissues. Pharyngeal Arch 1 pouch elongates to form tubotympanic recess tympanic cavity, mastoid antrum and auditory tube (Eustachian tube). Pharyngeal Arch 2 pouch forms the tonsillar sinus and is later mostly oblierated by palatine tonsil. Pharyngeal Arch 3 pouch forms the inferior parathyroid and thymus. Pharyngeal Arch 4 pouch forms the superior parathyroid, parafollicular cells of Thyroid. (More? [[Hearing_-_Middle_Ear_Development|Middle Ear]] | [[Endocrine - Thyroid Development‎|Thyroid]] | [[Endocrine - Parathyroid Development|Parathyroid]] | [[Endocrine - Thymus Development|Thymus‎]] | [[Endocrine System Development|Endocrine]] | [[Head Development]]
===pharyngotympanic tube===

:([[A#auditory tube|auditory tube]], [[E#eustachian tube|eustachian tube]], [[O#otopharyngeal tube|otopharyngeal tube]]) A narrow canal connecting the [[M#middle ear|middle ear]] space to the back of the oral cavity. The tube allows ventilation, protection and clearance for the middle ear cavity. Ventilation is the pressure equalization in the middle ear. Clearance is to allow fluid drainage from the middle ear. Embryonic origin is from the first pharyngeal pouch. In development, the canal is initially both horizontal, short and very narrow leading to poor drainage and easy blockage. (More? [[Hearing_-_Middle_Ear_Development|Middle Ear]] | [[Sensory_-_Hearing_and_Balance_Development|Hearing]] | [[Sensory_-_Hearing_Abnormalities|Hearing Abnormalities]])

===pharynx===

:(throat) Forms the initial segment of the upper respiratory tract divided anatomically into three regions: nasopharynx, oropharynx, and laryngopharynx (hypopharynx). Anatomically extends from the base of the skull to the level of the sixth cervical vertebra. (More? [[Respiratory System Development]])

{{Glossary}}
{{Footer}}

[[Category:Science-Undergraduate]] [[Category:Head]] [[Category:Pharyngeal Arch]]

Lecture - Head Development

2013-09-04T04:22:15Z

Z3283213:

= Head Development=
[[File:Stage14_sem2cl.jpg|right]]
== Introduction ==

[[File:Stage16-18 face.jpg|thumb|Human face development (Week 6 to 7)]]
The face is the anatomical feature which is truly unique to each human, though the basis of its general development is identical for all humans and similar to that seem for other species. The face has a complex origin arising from a number of head structures and sensitive to a number of teratogens during critical periods of its development. The related structures of upper lip and palate significantly contribute to the majority of face abnormalities.

The head and neck structures are more than just the face, and are derived from pharyngeal arches 1 - 6 with the face forming from arch 1 and 2 and the frontonasal prominence. Each arch contains similar Arch components derived from endoderm, mesoderm, neural crest and ectoderm. These components though will form different structures depending on their arch origin. Because the head contains many different structures also review notes on [[Sensory System Development|Special Senses]]), [[Respiratory System Development|Respiratory]], Integumentary (Teeth), [[Endocrine System Development|Endocrine]] (thyroid, parathyroid, pituitary, thymus) and [[Ultrasound]]- Cleft lip/palate.

==Lecture Plan==
* Origins of the head and neck tissues
* Pharyngeal arches
* Development of the face
* Development of the palate
* Development of the tongue and pharynx
* Derivatives of the pharyngeal arches and pouches
* Development of the skull

Lecture Date: 2013-09-10 Lecture Time: 12:00 Venue: Wallace Wurth LG03; Speaker: Professor Ken Ashwell

The Powerpoint file used to present this lecture is available as a pdf document [[Media:HeadDevelopment.pdf‎‎| HERE]]

A recording of the lecture will be available on Lectopia
[https://secured.learningandteaching.unsw.edu.au/lectopia/lectopiaLogin/default.cfm?ut=153 - Lectopia Login page]

[[File:Pharyngeal arch structure cartoon.gif]][[File:Stage13 pharyngeal arch excerpts.gif|300px]]

==Textbooks==
[[File:Pharyngeal_arch_cartilages.jpg|thumb]]
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00009-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00009-6 Chapter 9 – Pharyngeal Apparatus, Face, and Neck]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00018-7&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00018-7 Chapter 18 – Development of Eyes and Ears]
|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10016-8 Chapter 16 - Development of the Pharyngeal Apparatus and Face]

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10017-X Chapter 17 - Development of the Ears and Eyes]
|}

===Embryology===
{| border='0px'
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Head Links}}
|}

* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter Chapter 10 The Pharyngeal Apparatus pp201 - 240.
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 12 Development of the Head, the Neck, the Eyes, and the Ears pp349 - 418.

==Movies==

{| border='0px'
|-
| [[File:Stage16-18_face_01_icon.jpg|120px|link=Movie_-_Stage_16_to_18_Face]]
| [[File:Stage15-22 head 01 icon.jpg|120px|link=Movie_-_Stage_15_to_22_Head]]
| [[File:Face 001 icon.jpg|120px|link=Development_Animation_-_Face]]
| [[File:Palate_001 icon.jpg|120px|link=Development_Animation_-_Palate 1]]
| [[File:Palate_002 icon.jpg|120px|link=Development_Animation_-_Palate 2]]
| [[File:Tongue_001 icon.jpg|120px|link=Development_Animation_-_Tongue]]
|-
| [[Movie_-_Stage_16_to_18_Face|Face]]

Stage 16 to 18
| [[Movie_-_Stage_15_to_22_Head|Head]]

Stage 15 to 22
| [[Development_Animation_-_Face|Face]]
| [[Development_Animation_-_Palate 1|Palate 1]]
| [[Development_Animation_-_Palate 2|Palate 2]]
| [[Development_Animation_-_Tongue|Tongue]]
|-
|}

==Animation of Face Development==
{|
| <Flowplayer width="420" height="500" autoplay="true">Face_001.flv</Flowplayer>

[[Media:Face_001.mov|Quicktime version]]
|
'''Development of the Face'''

This animation shows a ventral view of development of the human face from approximately week 5 through to neonate.

The separate embryonic components that contribute to the face have been colour coded.

* '''Frontonasal Prominence (white)'''
* '''Frontonasal Prominence - Lateral nasal''' (purple)
* '''Frontonasal Prominence - Medial nasal''' (green)
* '''Pharyngeal Arch 1 - Maxillary prominence''' (yellow)
* '''Pharyngeal Arch 1 - Mandibular prominence''' (orange)
* '''Stomodeum (black)'''

The [[S#stomodeum|stomodeum]] is the primordial mouth region and a surface central depression lying between the forebrain bulge and the heart bulge. At the floor of the stomodeum indentation is the [[B#buccopharyngeal membrane|buccopharyngeal membrane]] (oral membrane).

Note the complex origin of the maxillary region (upper jaw) requiring the fusion of several embryonic elements, abnormalities of this process lead to [[C#cleft lip|cleft lip]] and [[C#cleft palate|cleft palate]].

See also the movie ([[Quicktime_Movie_-_Stage_16_to_18_Face|Quicktime]] | [[Quicktime_Movie_-_Stage_16_to_18_Face|Flash]]) showing a similar view of human embryo faces between [[Carnegie stage 16|Carnegie stage 16]] to [[Carnegie stage 18|18]].

'''Links:''' [[Quicktime Development Animation - Face]] | [[Media:Face_001.mov|Quicktime version]] | [[Head Development]]
|}

==Buccopharyngeal Membrane==

These images of the Stage 11 embryo show the breakdown of the buccopharyngeal membrane.
<gallery>
File:Stage11 sem4c.jpg|Low power ventral view of the Buccopharyngeal Membrane
File:Stage11 sem3c.jpg|Higher power ventrolateral view of the Buccopharyngeal Membrane
File:Stage11 sem2c.jpg|Close up view of the degenerating Buccopharyngeal Membrane
</gallery>

==The Pharynx==
[[File:Head arches cartoon.jpg|300px]]
[[File:Stage13 B2 excerpt.gif]]
[[File:Pharynx cartoon.jpg|300px]]

The cavity within the pharyngeal arches forms the pharynx.

* begins at the buccopharyngeal membrane (oral membrane), apposition of ectoderm with endoderm (no mesoderm between)
* expands behind pharyngeal arches
* narrows at glottis and bifurcation of gastrointestinal (oesophagus) and respiratory (trachea) systems
* regions on roof, walls and floor have important contributions to endocrine in oral and neck regions
* also contributes to tongue development

== Pharyngeal Arch Components ==
[[File:Pharyngeal arch structure cartoon.gif]]

Major features to identify for each: '''arch''', '''pouch''', '''groove''' and '''membrane'''. Contribute to the formation of head and neck and in the human appear at the 4th week. The first arch contributes the majority of upper and lower jaw structures.

==Pharyngeal Arch Development==

* '''branchial arch''' (Greek. ''branchia'' = gill)
* arch consists of all 3 trilaminar embryo layers:
# '''ectoderm''' - outside embryo surface (and neural crest in core)
# '''mesoderm''' - core of mesenchyme
# '''endoderm''' - inside pharynx

===Neural Crest ===
[[File:Head arches cartoon.jpg|thumb|neural crest migration]]
* Mesenchyme invaded by neural crest generating connective tissue components
* cartilage, bone, ligaments
* arises from midbrain and hindbrain region

===Arch Features===

Each arch contains: '''artery, cartilage, nerve and muscular''' component

Arches and Phanynx Form the face, tongue, lips, jaws, palate, pharynx and neck cranial nerves, sense organ components, glands

* Humans have 5 arches - 1, 2, 3, 4, 6 (Arch 5 does not form or regresses rapidly)
* from in rostro-caudal sequence, Arch 1 to 6 from week 4 onwards
* arch 1 and 2 appear at time of closure of cranial neuropore

* Face - mainly arch 1 and 2
* Neck components - arch 3 and 4 (arch 4 and 6 fuse)

{|
|
* arch
* groove
** externally separates each arch
*** also called a cleft
** only first pair persist as external auditory meatus
* pouch
** internally separates each arch
** pockets from the pharynx
* membrane
** ectoderm and endoderm contact regions
** only first pair persist as tympanic membrane
| [[File:Stage13_B2_excerpt.gif]]
|}

Pharyngeal Arch 1 (Mandibular Arch) has 2 prominences
* smaller upper- maxillary forms maxilla, zygomatic bone and squamous part of temporal
* larger lower- mandibular, forms mandible

Pharyngeal Arch 2 (Hyoid Arch)
* forms most of hyoid bone

Pharyngeal Arch 3 and 4
* neck structures

==Arch Arteries==
Blood Pathway: placental vein -> liver -> heart -> truncus arteriosus -> aortic sac -> '''arch arteries''' -> dorsal aorta -> placental artery

* Arch 1 - mainly lost, form part of '''maxillary artery'''
* Arch 2 - regresses to small '''stapedial arteries'''
* Arch 3 - '''common carotid arteries, internal carotid arteries'''
* Arch 4 - left forms part of '''aortic arch''', right forms part '''right subclavian artery'''
* Arch 6 - left forms part of '''left pulmonary artery''', right forms part of '''right pulmonary artery'''

==Arch Cartilage==
[[File:Meckel.jpg|thumb|Meckel's cartilage, first pharyngeal arch]]
[[File:Pharyngeal_arch_cartilages.jpg|thumb|Pharyngeal arch cartilages]]
* Arch 1 - Meckel's cartilage, horseshoe shaped
** dorsal ends form malleus and incus
** midpart forms ligaments (ant. malleus, sphenomandibular)
** ventral part forms mandible template
<gallery>
File:Gray0178.jpg|Embryo CRL 24 mm outer aspect (week 8)
File:Gray0178.jpg|Embryo CRL 24 mm inner aspect
File:Gray0180.jpg|Fetus CRL 95 mm outer aspect (week 13-14)
File:Gray0181.jpg|Fetus CRL 95 mm inner aspect
</gallery>
* Arch 2 - Reichert's cartilage
** dorsal ends form '''stapes''' and '''temporal bone styloid process'''
** ventral part ossifies to form '''hyoid bone''' components (lesser cornu and superior body)

* Arch 3 - forms '''greater cornu''' and '''inferior part of hyoid'''

* Arch 4&6 - form '''laryngeal cartilages''', except epiglottis (from hypobranchial eminence)

==Arch Muscle==
* Arch 1 - '''muscles of mastication''', mylohyoid, tensor tympanic, anterior belly digastric
* Arch 2 - '''muscles of facial expression''', stapedius, stylohyoid, posterior belly digastric
* Arch 3 - stylopharyngeus
* Arch 4&6 - crycothyroid, pharynx constrictors, larynx muscles, oesophagus (st. muscle)

==Arch Nerve==
* Arch 1 - '''CN V''' trigeminal, caudal 2/3 maxillary and mandibular, cranial 1/3 sensory nerve of head and neck, mastication motor
* Arch 2 - '''CN VII''' facial
* Arch 3 - '''CN IX''' glossopharyngeal
* Arch 4&6 - '''CN X''' vagus, arch 4 - superior laryngeal, arch 6 - recurrent laryngeal

==Arch Pouches==
{|
|
* Arch 1 - elongates to form '''tubotympanic recess''', tympanic cavity, mastoid antrum, eustachian tube
* Arch 2 - forms tonsillar sinus, mostly oblierated by palatine tonsil
* Arch 3 - forms '''inferior parathyroid''' and '''thymus'''
* Arch 4 - forms '''superior parathyroid''', '''parafollicular cells of thyroid'''
| [[File:Pharyngeal_pouches.jpg]]
|}

==Thyroid Gland ==
[[File:Stage13 and 22 thyroid development.jpg|thumb|Stage13 and 22 thyroid development]]
* not a pouch structure
* first endocrine organ to develop day 24
* from '''floor of pharynx'''
* descends thyroglossal duct (which closes)
* upper end at foramen cecum

==Anterior Pituitary==
[[File:Historic-pituitary.jpg|thumb|Pituitary]]
* not a pouch structure
* boundary epitheilal '''ectoderm''' in the roof of the pharynx
* forms a pocket (Rathke's pouch) that comes into contact with the ectoderm of developing brain.
** Rathke's pouch is named after German embryologist and anatomist Martin Heinrich Rathke (1793 - 1860).

==Face Development==
[[File:Stage16-18 face animation.gif|right]]
Begins week 4 centered around stomodeum, external depression at oral membrane

5 initial primordia from neural crest mesenchyme
* single frontonasal prominence (FNP) - forms forehead, nose dorsum and apex
* nasal placodes develop later bilateral, pushed medially
* paired maxillary prominences - form upper cheek and upper lip
* paired mandibular prominences - lower cheek, chin and lower lip

[[:File:Face animation.gif]]

==Head/Skull==

* '''chondrocranium''' forms base of skull
** in lower vertebrates encases brain
* '''cranial vault'''
** calveria
* '''facial skeleton'''
** pharyngeal arches

==Sensory Placodes ==
'''MH -''' will cover sensory placodes in Senses Lecture.

* During week 4 a series of thickened surface ectodermal patches form in pairs rostro-caudally in the head region.
** Recent research suggests that all sensory placodes may arise from common panplacodal primordium origin around the neural plate, and then differentiate to eventually have different developmental fates.
* These sensory placodes will later contribute key components of each of our special senses (vision, hearing and smell).
* Other species have a number of additional placodes which form other sensory structures (fish, lateral line receptor).
* Note that their initial postion on the developing head is significantly different to their final position in the future sensory system

===Otic placode===
* in the stage 13/14 embryo (shown below) the otic placode has sunk from the surface ectoderm to form a hollow epithelial ball, the otocyst, which now lies beneath the surface surrounded by mesenchyme (mesoderm). The epithelia of this ball varies in thickness and has begun to distort, it will eventually form the inner ear membranous labyrinth.

{|
| [[File:Stage12_sem6.jpg|400px]]

Stage 12 Embryo - otic placode
| [[File:Stage13_otocyst.jpg|400px]]

Stage 13 Embryo - otocyst
|}

===Lens placode===
[[File:Stage14_sem2l.jpg|thumb|Stage 14 Embryo - - optic and nasal placodes]]
lies on the surface, adjacent to the outpocketing of the nervous system (which will for the retina) and will form the lens.

===Nasal placode===
has 2 components (medial and lateral) and will form the nose olefactory epithelium.

==Head Growth==
[[File:Fetal_head_lateral.jpg|thumb|Fetal Head (12 weeks) showing bone and cartilage]]
* continues postnatally - fontanelle allow head distortion on birth and early growth
* bone plates remain unfused to allow growth, puberty growth of face

===Skull Overview===
[[File:Keibel_Mall_321.jpg|thumb|Lateral view of the cranium of a human fetus 80 mm long.]]
'''Chondrocranium''' - formed from paraxial mesoderm
* cranial end of vertebral column
* modified vertebral elements
* occipital and cervical sclerotome
* bone preformed in cartilage (endochondrial ossification)

'''Cranial Vault and Facial Skeleton''' - formed from neural crest
* muscle is paraxial mesoderm
* somitomeres and occipital somites

Calveria - bone has no cartilage (direct ossification of mesenchyme)
* bones do not fuse, fibrous sutures 1. allow distortion to pass through birth canal 2. allow growth of the brain
* 6 fontanelles, posterior closes at 3 months, anterior closes at 18 months
{| class="prettytable"
| [[File:Skull anterior.gif]]
| [[File:Skull_superior.gif]]
| [[File:Skull lateral view.gif]]

|-
| anterior view
| superior view
| lateral view

|-
| showing anterior fontenelle, sutures, mandible
| showing anterior fontenelle, sutures
| showing suture, mandible

|}

==Palate==
The palate has two key stages of development during embryonic and an early fetal involving the fusion of structures (epithelia to mesenchymal).

=== Embryonic===
Primary palate, fusion in the human embryo between stage 17 and 18, from an epithelial seam to the mesenchymal bridge.

[[File:Stage17-18 Primary palate.gif]]

===Fetal===
[[File:Stage_22_image_061.jpg|thumb]]
Secondary palate, fusion in the human embryo in week 9. This requires the early palatal shelves growth, elevation and fusion during the early embryonic period. The fusion event is to both each other and the primary palate. [[:File:Palatal shelves animation.gif|palatal shelf elevation]] | [[:File:palate.gif|secondary palate]]

==Ear Auricles==

* form from 6 hillocks (week 5)
* 3 on each of arch 1 and 2

==Tongue Development==
[[File:Tongue1.png|200px]] [[File:Tongue2.png|200px]] [[File:Tongue3.png|200px]]

* '''Ectoderm''' of the first arch surrounding the stomodeum forms the epithelium lining the buccal cavity.
** Also the salivary glands, enamel of the teeth, epithelium of the body of the tongue.
* Tongue develops "inside" the floor of the oral cavity
** it is not readily visible in the external views of the embryonic (Carnegie) stages of development.

* Contributions from all arches, which changes with time
* begins as swelling rostral to foramen cecum, '''median tongue bud'''

** Arch 1 - oral part of tongue (ant 3/2)
** Arch 2 - initial contribution to surface is lost
** Arch 3 - pharyngeal part of tongue (post 1/3)
** Arch 4 - epiglottis and adjacent regions

[[:File:tongue.gif|tongue development animation]]

===Tongue muscle===
[[File:Tongue-muscle.jpg|thumb|tongue muscle]]
* Tongue muscles originate from the somites. Tongue muscles develop before masticatory muscles and is completed by birth.
* Masticatory muscles originate from the somitomeres. These muscles develop late and are not complete even at birth.

===Salivary Glands===

* epithelial buds in oral cavity (wk 6-7) extend into mesenchyme
* parotid, submandibular, sublingual

== Abnormalities ==
===Cleft Lip and Palate===
* 300+ different abnormalities, different cleft forms and extent, upper lip and ant. maxilla, hard and soft palate

====Cleft Palate====
* Cleft palate has the International Classification of Diseases code 749.0.
* In Australia the national rate (1982-1992) for this abnormalitity in births was 4.8 - 6/10,000 births, which represented 1,530 infants 5.5% were stillborn and 11.5% liveborn died during neonatal period and slightly more common in twin births than singleton.

====Cleft Lip====
* The International Classification of Diseases code 749.1 for isolated cleft lip and 749.2 for cleft lip with cleft palate.
* In Australia the national rate (1982-1992) for this abnormalitity was 8.1 - 9.9 /10,000 births. Of 2,465 infants 6.2% were stillborn and 7.8% liveborn died during neonatal period and the rate was similar in singleton and twin births.

===First Arch Syndrome ===
* There are 2 major types of associated first arch syndromes, Treacher Collins (Mandibulofacial dysostosis) and Pierre Robin (Pierre Robin complex or sequence), both result in extensive facial abnormalites.

==== Treacher Collins Syndrome====

====Pierre Robin Syndrome ====
* Hypoplasia of the mandible, cleft palate, eye and ear defects.
* Initial defect is small mandible (micrognathia) resulting in posterior displacement of tongue and a bilateral cleft palate.

===DiGeorge Syndrome===
* absence of thymus and parathyroid glands, 3rd and 4th pouch do not form
* disturbance of cervical neural crest migration

===Cysts===
* Many different types

=== Facial Clefts===
** extremely rare
* Holoprosencephaly
** shh abnormality

===Maternal Effects ===
* Retinoic Acid - present in skin ointments
*1988 associated with facial developmental abnormalities

===Fetal Alcohol Syndrome===
[[File:FASface.jpg|left]]
Due to alcohol in early development (week 3+) leading to both facial and neurological abnormalities
* lowered ears, small face, mild+ retardation
* Microcephaly - leads to small head circumference
* Short Palpebral fissure - opening of eye
* Epicanthal folds - fold of skin at inside of corner of eye
* Flat midface
* Low nasal bridge
* Indistinct Philtrum - vertical grooves between nose and mouth
* Thin upper lip
* Micrognathia - small jaw

Exposure of embryos in vitro to ethanol simulates premature differentiation of prechondrogenic mesenchyme of the facial primordia (1999)

[http://embryology.med.unsw.edu.au/Defect/page5a.htm Fetal Alcohol Syndrome]

== Table - Structures derived from Arches ==

{| class="prettytable" border=1
| '''Arch'''
| '''Nerve'''
| '''Skeletal Structures'''
| '''Muscles'''
| '''Ligaments'''

|-
| 1 (maxillary/mandibular)
| trigeminal (V)
| mandible, maxilla, malleus, incus
|  
| ant lig of malleus, sphenomandibular ligament

|-
| 2 (hyoid)
| facial (VII)
| stapes, styloid process, lesser cornu of hyoid, upper part of body of hyoid bone
|  
| stylohyoid ligament

|-
| 3
| glossopharyngeal (IX)
| greater cornu of hyoid, lower part of body of hyoid bone
|  
|

|-
| 4 & 6
| superior laryngeal and recurrent laryngeal branch of vagus (X)
| thyroid, cricoid, arytenoid, corniculate and cuneform cartilages
|  
|

|}

=== Structures derived from Arches ===

{| class="prettytable" border=1
| '''Arch'''
| '''Nerve'''
| '''Skeletal Structures'''
| '''Muscles'''
| '''Ligaments'''

|-
| 1 (maxillary/mandibular)
| trigeminal (V)
| mandible, maxilla, malleus, incus
|  
| ant lig of malleus, sphenomandibular ligament

|-
| 2 (hyoid)
| facial (VII)
| stapes, styloid process, lesser cornu of hyoid, upper part of body of hyoid bone
|  
| stylohyoid ligament

|-
| 3
| glossopharyngeal (IX)
| greater cornu of hyoid, lower part of body of hyoid bone
|  
|

|-
| 4 & 6
| superior laryngeal and recurrent laryngeal branch of vagus (X)
| thyroid, cricoid, arytenoid, corniculate and cuneform cartilages
|  
|

|}
'''Skeletal Structures'''

{| class="prettytable" border=1
| [[Image:mandible_sm.jpg]]
| mandible

|-
| [[Image:hyoid_bone_sm.jpg]]
| hyoid

|-
| [[Image:larynx_cartilage_sm.jpg]]
|  

|}

=== Structures derived from Pouches ===
Each pouch is lined with endoderm and generates specific structures.

{| class="prettytable" border=1
| <center>'''POUCH'''</center>
| '''Overall Structure'''
| '''Specific Structures'''

|-
| <center>1</center>
| tubotympanic recess
| tympanic membrane, tympanic cavity, mastoid antrum, auditory tube

|-
| <center>2</center>
| intratonsillar cleft
| crypts of palatine tonsil, lymphatic nodules of palatine tonsil

|-
| <center>3</center>
| inferior parathyroid gland, thymus gland
|

|-
| <center>4</center>
| superior parathyroid gland, ultimobranchial body
|

|-
| <center>5</center>
| becomes part of 4th pouch
|

|}

=== Structures derived from Grooves ===
Only the '''first''' '''groove''' differentiates into an adult structure and forms part of the external acoustic meatus.

=== Structures derived from Membranes ===
At the bottom of each groove lies the membrane which is formed from the contact region of ectodermal groove and endodermal pouch. Only the '''first''' '''membrane''' differentiates into an adult structure and forms the tympanic membrane.

== References ==
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter Chapter 10 The Pharyngeal Apparatus pp201 - 240.
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 12 Development of the Head, the Neck, the Eyes, and the Ears pp349 - 418.

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.43 Figure 1.3. Pharyngeal arches] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.table.3135 Table 13.2. Some derivatives of the pharyngeal arches] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3109#3133 The Cranial Neural Crest]

* '''Madame Curie Bioscience Database''' Chapters taken from the Madame Curie Bioscience Database (formerly, Eurekah Bioscience Database) [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A53006 Cranial Neural Crest and Development of the Head Skeleton] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=ch2957 Neural Crest Cells and the Community of Plan for Craniofacial Development: Historical Debates and Current Perspectives]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=pharyngeal_arch pharyngeal arch] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=head_development head development] | [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=face_development face development]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=pharyngeal_arch pharyngeal arch] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=head_development head development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=face_development face development] |

==Movies==
{| border='0px'
|-
| [[File:Face 001 icon.jpg|90px|link=Development_Animation_-_Face]]
| [[File:Palate_001 icon.jpg|90px|link=Development_Animation_-_Palate 1]]
| [[File:Palate_002 icon.jpg|90px|link=Development_Animation_-_Palate 2]]
| [[File:Tongue_001 icon.jpg|90px|link=Development_Animation_-_Tongue]]
|-
| [[Development_Animation_-_Face|Face]]
| [[Development_Animation_-_Palate 1|Palate 1]]
| [[Development_Animation_-_Palate 2|Palate 2]]
| [[Development_Animation_-_Tongue|Tongue]]
|-
|}

== External Links ==
'''Embryo Images Unit:''' [http://www.med.unc.edu/embryo_images/ Embryo Images Online] | [http://www.med.unc.edu/embryo_images/unit-hednk/hednk_htms/hednktoc.htm Craniofacial Development] | [http://www.med.unc.edu/embryo_images/unit-hednk/hednk_htms/hednk001.htm Cell Populations] | [http://www.med.unc.edu/embryo_images/unit-hednk/hednk_htms/hednk007.htm Pharyngeal Arches] | [http://www.med.unc.edu/embryo_images/unit-hednk/hednk_htms/hednk024.htm Tongue] | [http://www.med.unc.edu/embryo_images/unit-hednk/hednk_htms/hednk026.htm Nose and Upper Lip] | [http://www.med.unc.edu/embryo_images/unit-hednk/hednk_htms/hednk033.htm Palate Development]

'''Research Labs:''' [http://www.weizmann.ac.il/Biological_Regulation/tzahor/research.html tzahor lab]

==Terms==

===palate===

:The roof of the mouth (oral cavity) a structure which separates the oral from the nasal cavity. Develops as two lateral palatal shelves which grow and fuse in the midline. Initally a primary palate forms with fusion of the maxillary processes with the nasal processes in early face formation. Later the secondary palate forms the anterior [[H#hard_palate|hard palate]] which will ossify and separate the oral and nasal cavities. The posterior part of the palate is called the soft palate (velum, muscular palate) and contains no bone. Abnormalities of palatal shelf fusion can lead to [[C#cleft_palate|cleft palate]]. (More? [[Head Development|Head]] | [[Head_Development_-_Abnormalities|Head Abnormalities]] | [http://www.nlm.nih.gov/medlineplus/cleftlipandpalate.html Medline Plus - Cleft Lip and Palate])

===palatogenesis===

:The process of palate formation, divided into primary and secondary palate development. (More? [[Head Development|Head]] | [[Head_Development_-_Abnormalities|Head Abnormalities]] | [http://www.nlm.nih.gov/medlineplus/cleftlipandpalate.html Medline Plus - Cleft Lip and Palate])

===pharyngeal arch===

:([[B#branchial arch|branchial arch]], Greek, ''branchial'' = gill) These are a series of externally visible anterior tissue bands lying under the early brain that give rise to the structures of the head and neck. In humans, five arches form (1,2,3,4 and 6) but only four are externally visible on the [[E#embryo|embryo]]. Each arch has initially identical structures: an internal endodermal pouch, a mesenchymal ([[M#mesoderm|mesoderm]] and [[N#neural crest|neural crest]]) core, a membrane ([[E#endoderm|endoderm]] and [[E#ectoderm|ectoderm]]) and external cleft ([[E#ectoderm|ectoderm]]). Each arch mesenchymal core also contains similar components: blood vessel, nerve, muscular, cartilage. Each arch though initially formed from similar components will differentiate to form different head and neck structures. (More? | [[Head Development]] | [[Endocrine System Development|Endocrine]] | [[Neural Crest Development|Neural Crest]])

===pharyngeal arch artery===

:Each early developing pharyngeal arch contains a lateral pair of arteries arising from the aortic sac, above the heart, and running into the dorsal aorta. later in development these arch arteries are extensively remodelled to form specific components of the vascular system. Pharyngeal Arch 1 arteries are mainly lost and forms part of maxillary artery. Pharyngeal Arch 2 arteries remains to form the stapedial arteries. Pharyngeal Arch 3 arteries forms the common carotid arteries, internal carotid arteries in the neck. Pharyngeal Arch 4 arteries will form part of aortic arch (left arch artery) and part right subclavian artery (right arch artery) Pharyngeal Arch 6 arteries form part of left pulmonary artery (left arch artery) and part of right pulmonary artery (right arch artery). (More? | [[Head Development]] | [[Cardiovascular System Development|Cardiovascular]])

===pharyngeal arch cartilage===

:Each early developing pharyngeal arch contains a horseshoe shaped band of cartilage that acts as a template and contributes to the development of head and neck bony and cartilagenous features, including the middle ear bones. Pharyngeal Arch 1 cartilage (Meckel‚Äôs cartilage) dorsal ends form malleus and incus midpart forms ligaments (ant. malleus, sphenomandibular) ventral part forms mandible template. Pharyngeal Arch 2 cartilage (Reichert‚Äôs cartilage) dorsal ends form stapes and Temporal bone styloid process, ventral part ossifies to form hyoid bone components, lesser cornu and superior body. Pharyngeal Arch 3 cartilage forms hyoid components, greater cornu and inferior part of hyoid. Pharyngeal Arch 4 and 6 cartilage forms laryngeal cartilages except epiglottis (from hypobranchial eminence). (More? [[Head Development]] | [[Hearing_-_Middle_Ear_Development|Middle Ear]])

===pharyngeal arch nerve===

:Each early developing pharyngeal arch contains the developing cranial nerves, as a pair, within the arch mesenchyme. Each cranial nerve is numbered (roman numeral) in rostrocaudal sequence and also has a specific name. The cranial nerve within each arch often relates to the other structures formed from taht arch. Pharyngeal Arch 1 contains the trigeminal nerve (CN V, cranial nerve 5). Pharyngeal Arch 2 contains the facial nerve (CN VII, cranial nerve 7). Pharyngeal Arch 3 contains the glossopharyngeal nerve (CN IX, cranial nerve 9) Pharyngeal Arch 4 and 6 contains the Vagus (CN X cranial nerve 10), forming the adult superior laryngeal and recurrent laryngeal branches. (More? | [[Head Development]] | [[Neural System Development|Neural]] | [[Neural Crest Development|Neural Crest]])

===pharyngeal arch pouch===

:An out-pocketing of the [[E#endoderm|endoderm]] lined pharynx occurring between each developing pharyngeal arch. Each of the pharyngeal arch pouches contributes different components of the head and neck, either cavities or endocrine tissues. Pharyngeal Arch 1 pouch elongates to form tubotympanic recess tympanic cavity, mastoid antrum and auditory tube (Eustachian tube). Pharyngeal Arch 2 pouch forms the tonsillar sinus and is later mostly oblierated by palatine tonsil. Pharyngeal Arch 3 pouch forms the inferior parathyroid and thymus. Pharyngeal Arch 4 pouch forms the superior parathyroid, parafollicular cells of Thyroid. (More? [[Hearing_-_Middle_Ear_Development|Middle Ear]] | [[Endocrine - Thyroid Development‎|Thyroid]] | [[Endocrine - Parathyroid Development|Parathyroid]] | [[Endocrine - Thymus Development|Thymus‎]] | [[Endocrine System Development|Endocrine]] | [[Head Development]]
===pharyngotympanic tube===

:([[A#auditory tube|auditory tube]], [[E#eustachian tube|eustachian tube]], [[O#otopharyngeal tube|otopharyngeal tube]]) A narrow canal connecting the [[M#middle ear|middle ear]] space to the back of the oral cavity. The tube allows ventilation, protection and clearance for the middle ear cavity. Ventilation is the pressure equalization in the middle ear. Clearance is to allow fluid drainage from the middle ear. Embryonic origin is from the first pharyngeal pouch. In development, the canal is initially both horizontal, short and very narrow leading to poor drainage and easy blockage. (More? [[Hearing_-_Middle_Ear_Development|Middle Ear]] | [[Sensory_-_Hearing_and_Balance_Development|Hearing]] | [[Sensory_-_Hearing_Abnormalities|Hearing Abnormalities]])

===pharynx===

:(throat) Forms the initial segment of the upper respiratory tract divided anatomically into three regions: nasopharynx, oropharynx, and laryngopharynx (hypopharynx). Anatomically extends from the base of the skull to the level of the sixth cervical vertebra. (More? [[Respiratory System Development]])

{{Glossary}}
{{Footer}}

[[Category:Science-Undergraduate]] [[Category:Head]] [[Category:Pharyngeal Arch]]

File:NeuralCrest.pdf

2013-09-04T04:18:57Z

Z3283213:

File:HeadDevelopment.pdf

2013-09-04T04:18:30Z

Z3283213:

Lecture - Neural Crest Development

2013-09-04T03:16:59Z

Z3283213:

== Introduction ==
[[File:Stage11 sem21.jpg|thumb|300px|Human embryo neural crest cells ([[Week 4]], [[Carnegie stage 11|stage 11]])]]
The neural crest are bilaterally paired strips of cells arising in the ectoderm at the margins of the neural tube. These cells migrate to many different locations and differentiate into many cell types within the embryo. This means that many different systems (neural, skin, teeth, head, face, heart, endocrine, gastrointestinal tract) will also have a contribution fron the neural crest cells.

In the body region, neural crest cells also contribute the peripheral nervous system (both neurons and glia) consisting of sensory ganglia (dorsal root ganglia), sympathetic and parasympathetic ganglia and neural plexuses within specific tissues/organs.

In the head region, neural crest cells migrate into the pharyngeal arches (as shown in movie below) forming '''ectomesenchyme''' contributing tissues which in the body region are typically derived from mesoderm (cartilage, bone, and connective tissue). General neural development is also covered in Neural Notes.

==Lecture Objectives==
[[File:Carnegie stage 13 caudal trunk.jpg|thumb|Human Embryo (Carnegie stage 13) caudal trunk<ref><pubmed>18689800</pubmed>| [http://hmg.oxfordjournals.org/cgi/content/full/17/21/3411 Hum Mol Genet.]</ref>]]
* Understand the structures derived from ectoderm.
* Understand the formation of neural folds.
* Identify the initial location of neural crest cells and pathways of neural crest migration throughout the embryo.
* To know the major tissues to which neural crest cells contribute.
* To know how abnormalities in development that result from abnormal neural crest cell migration.

[https://secured.learningandteaching.unsw.edu.au/lectopia/lectopiaLogin/default.cfm?ut=153 - Lectopia Login page]

Lecture Date: 2013-09-10 Lecture Time: 16:00 Venue: BioMed E; Speaker: Professor Ken Ashwell
|}

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00017-5&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00017-5 Chapter 17 – Nervous System]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00009-6&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00009-6 Chapter 9 – Pharyngeal Apparatus, Face, and Neck]

|}
===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10010-7 Chapter 10 - Development of the Peripheral Nervous System]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10016-8 Chapter 16 - Development of the Pharyngeal Apparatus and Face]
|-
| [[File:Logo.png|80px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.

{{Neural Crest Links}}
|}

==Neural Crest Migration in the Head==
{| border='0px'
|-
| <Flowplayer width="408" height="320" autoplay="true">Chicken-neural crest migration 01.flv</Flowplayer>
| valign="top" |[[File:Chicken-neural-crest-migration-01.jpg|300px]]
Chicken embryo sequence shows the migration of DiI-labeled neural crest cells towards the branchial arches as the embryo.
White rings indicate migration of individual cells. Each image represents 10 confocal sections separated by 10 microns.

|-
|}

Movie Source: Original Neural Crest movies kindly provided by Paul Kulesa.

'''Related Movies:''' [[Movie - Chicken Neural Crest Migration 01|Migration 01]] | [[Movie - Chicken Neural Crest Migration 02|Migration 02]] | [[Movie - Chicken Neural Crest Migration 03|Migration 03]] | [[Movie - Chicken Neural Crest Migration 04|Migration 04]] | [[Movie - Chicken Neural Crest Migration 05|Migration 05]] | [[Movie - Chicken Neural Crest Migration 06|Migration 06]] | [[Movie - Chicken Neural Crest Migration 07|Migration 07]]

==Early Development and Neural Derivatives==
[[File:Neuralplate cartoon.png|right]]
* bilaminar embryo- hypoblast
* trilaminar embryo - ectoderm layer
** neural plate - neural groove - neural tube and neural crest
* cranial expansion of neural tube - central nervous system
* caudal remainder of neural tube - spinal cord

Neural Crest - contributes both neural and non-neural cells
* dorsal root ganglia
* parasympathetic / sympathetic ganglia.

==Neural Crest Origin==
* lateral region of neural plate
* dorsal neural fold->tube

Two main embryo regions
* '''Head''' (CNS level) - differentiate slightly earlier, mesencephalic region of neural folds.
* '''Body''' (spinal cord level) - lateral edges of fused neural tube.

== Neural Crest Generation ==

* cranial region - Begins when still neural fold
* spinal cord - from day 22 until day 26
** after closure of caudal neuropore
** rostro-caudal gradient of differentiation

Studies using the chicken model demonstrated that they are not a segregated population. Interactions between the neural plate and epidermis can generate neural crest cells, since juxtaposition of these tissues at early stages results in the formation of neural crest cells at the interface.

At cranial levels, neuroepithelial cells can regulate to generate neural crest cells when the endogenous neural folds are removed, probably via interaction of the remaining neural tube with the epidermis.

Progenitor cells in the neural folds are multipotent, having the ability to form multiple ectodermal derivatives, including epidermal, neural crest, and neural tube cells the neural crest is an induced population that arises by interactions between the neural plate and the epidermis.

The competence of the neural plate to respond to inductive interactions changes as a function of embryonic age.

(Text from: Bronner-Fraser M PNAS 1996 Sep 3;93(18):9352-7)

== Neural Crest Derivatives ==
Neural crest progenitor cells migrate throughout the embryo and give rise to many different adult cells.

This Includes: ganglia cranial, dorsal root, sympathetic trunk, celiac, renal, plexus in GIT, glia, schwann cells, melanocytes (skin), and adrenal medulla (chromaffin cells).

In the head region neural crest also gives rise to a number of connective tissue structures.

==Neural Crest - Head==
See also [[Lecture - Head Development]]
[[File:Mouse_eye_TGF-beta_model.jpg|thumb|Eye Development]]
[[File:Mouse-E10.5 ganglia Sox10.jpg|thumb|Mouse E10.5- neural crest cell distribution (black)]]

Mesencephalon and caudal Proencephalon

* parasympathetic ganglia CN III
* connective tissue around eye and nerve
* head mesenchyme
* neural connective tissue (meninges)

Mesencephalon and Rhombencephalon

* pharayngeal arches
** look at practical notes on neck and head.
* cartilage rudiments (nose, face, middle ear)
* face and facial skeleton
* dermis, smooth muscle and fat
* odontoblasts of developing teeth

Rhombencephalon

* C cells of thyroid
* cranial nerve ganglia
* neurons and glia
* parasympathetic of VII, IX, X
* sensory ganglia of V, VII, VIII, IX, X

==Neural Crest - Peripheral Nervous System==

* peripheral nervous system
* dorsal root ganglia (sensory N)
* parasympathetic ganglia
* sympathetic ganglia
* motoneurons in both ganglia
* all associated glia

== Neural Crest Migration ==
===Head===
[[File:Hindbrain neural crest migration.jpg|thumb|Hindbrain neural crest migration]]
{| border='0px'
|+ '''Neural crest migration in the head in chicken''' ([[Movies_-_Chicken_Neural_Crest|chicken neural crest movies overview]])
|-
| [[File:Chicken-neural-crest-migration-01.jpg|90px|link=Movie - Chicken Neural Crest Migration 01]]
| [[File:Chicken-neural-crest-migration-02.jpg|90px|link=Movie - Chicken Neural Crest Migration 02]]
| [[File:Chicken-neural-crest-migration-03.jpg|90px|link=Movie - Chicken Neural Crest Migration 03]]
| [[File:Chicken-neural-crest-migration-04.jpg|90px|link=Movie - Chicken Neural Crest Migration 04]]
| [[File:Chicken-neural-crest-migration-05.jpg|90px|link=Movie - Chicken Neural Crest Migration 05]]
| [[File:Chicken-neural-crest-migration-06.jpg|90px|link=Movie - Chicken Neural Crest Migration 06]]
| [[File:Chicken-neural-crest-migration-07.jpg|90px|link=Movie - Chicken Neural Crest Migration 07]]
|}

[[File:Mouse_head_E9-neural_crest_GFP.jpg|300px||Mouse_head_E9-neural_crest_GFP]] [[File:Hindbrain neural crest migration.jpg|300px|Hindbrain neural crest migration]] [[File:Mouse-E9.5-Sox10.jpg|300px|Mouse-E9.5-Sox10.jpg]]
===Trunk===

===Cardiac Outflow Tract===

[[File:Cardiac_Neural_Crest_Migration.jpg|300px]]

[[File:Human neural crest cell migration-in vitro.jpg|thumb|Human neural crest cell migration (in vitro)<ref><pubmed>18689800</pubmed>| [http://hmg.oxfordjournals.org/cgi/content/full/17/21/3411 Hum Mol Genet.]</ref>]]
[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3118 Figure 13.2. Neural crest cell migration in the trunk of the chick embryo]
* Neural crest at the level of the body have two general migration pathways, defined by the position of the somite
** medial pathway - between the neural tube and the somite
** lateral pathway - between the somite and the body wall
[[File:Trunk neural crest migration.jpg|thumb|Trunk neural crest migration]]
* A recent study of guidance of neural crest cells (NCC) in mice show migrate 3 specific pathways.
** SEMA3A and its receptor neuropilin 1 (NRP1) - act as repulsive guidance cues
** migration pathway did not affect specification - differs from the concept of migration pathway specifying the neural crest cell differentiation pathway

Neural crest at the level of the head have a different migration pathway. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3134 Figure 13.7. Cranial neural crest cell migration in the mammalian head]

===Sympathetic Ganglia and Adrenal Medulla===
[[File:Adrenal_medulla.jpg|300px]]

[[Media:Adrenal_medulla.mov]]

===Enteric nervous system===

[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A63004&rendertype=figure&id=A63009 Figure 1. Diagram of an E10 embryo showing the origins of neural crest cells that colonize the developing gastrointestinal tract]

==Historic Migration Experiments==
Key early experiments in understanding the pattern of neural crest migration were carried out by [[Embryology_History_-_Nicole_Le_Douarin|LeDouarin]] in the 1980's (see Development of the peripheral Nervous system from the neural crest, Ann Rev Cell Biol 4 p375)
[http://www.sdbonline.org/archive/dbcinema/ledouarin/ledouarin.html Quail-Chick Chimeras] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.63 Figure 1.11. Neural crest cell migration Chimera experiment]

These transplantation studies in chicken/quail chimeras utilised the different nucleoli appearance of cells to differentiate different species. Thus transplanation and subsequent histological processing allowed identification of the migration path and final destination of transplanted neural crest cells.

Similar later experiments have now been carried out using the neural crest cells molecularly tagged with (LacZ).

==Abnormalities==

===Neuroblastoma===
[[File:Neuroblastoma.jpg|thumb|Neuroblastoma]]
[[File:Childhood cancer survival rates.jpg|thumb|Childhood cancer survival rates]]

[http://www.ncbi.nlm.nih.gov/omim/256700 OMIM - Neuroblastoma]

===Digeorge Syndrome (DGS)===
[[File:Digeorge chromosome22.jpg|thumb|Digeorge chromosome 22]]
* DiGeorge syndrome is the most frequent microdeletion syndrome in humans caused by a hemizygous deletion (1.5 to 3.0-Mb) of chromosome 22q11.2.
* Velo-cardio-facial syndrome, Hypoplasia of thymus and parathyroids, third and fourth pharyngeal pouch syndrome.
* Abnormalities: cardiovascular, thymic and parathyroid, craniofacial anomalies, renal anomalies, hypocalcemia and immunodeficiency.

===Intestinal Aganglionosis===
[[File:Megacolon surgery.gif]]
[[File:Megacolon stoma.gif]]
* Intestinal Aganglionosis, Hirschsprung's Disease or Megacolon
* lack of enteric nervous system (neural ganglia) in the intestinal tract responsible for gastric motility (peristalsis).
* severity is dependent upon the amount of the GIT that lacks intrinsic ganglia, due to developmental lack of neural crest migration into those segments.
* first indication in newborns is an absence of the first bowel movement, other symptoms include throwing up and intestinal infections.
* Clinically this is detected by one or more tests (barium enema and x ray, manometry or biopsy) and can currently only be treated by surgery. A temoporary ostomy (Colostomy or Ileostomy) with a stoma is carried out prior to a more permanent pull-through surgery.

===Melanoma===
[[File:Melanoma.jpg]]
* In Australia each year 8,800 people are diagnosed with melanoma, and almost 1000 people die (Data, Cancer Council Australia).
* Two different findings on the reprogramming of melanoma cells, which have a neural crest origin, when transplanted between species into embryos.

[http://www.melanoma.com/staging.html Melanoma staging]

===Neurofibromatosis Type 1 (NF1)===

* Neurofibromatosis Type 1 (von Recklinghausen) occurs in 1 in 3,000 to 4,000 people with characteristic skin blemishes forming in early childhood.
* Multiple ''café-au-lait'' spots (flat skin patches darker than the surrounding area) appear in early childhood which increase in both size and number with age.
* tumors can develop along nerves in the skin, brain, and other parts of the body. In the iris of the eye, Lisch nodules (benign growths) also appear
:(French, ''café-au-lait'' = coffee with milk)

[http://atlasgeneticsoncology.org/Tumors/NeurofibromaID5098.html Atlas of Genetics and Cytogenetics in Oncology- Neurofibroma]

===Tetralogy of Fallot===
Cardiac abnormality possibly stemming from abnormal [[N#neural crest|neural crest]] migration. Named after Etienne-Louis Arthur Fallot (1888) who described it as "''la maladie blue''". (More? [[Cardiovascular System Development]] | [[Cardiac_Embryology|Cardiac Tutorial]] | [[2009_Lecture_21|Lecture - Heart]] | [[Cardiovascular System - Abnormalities]])

===Treacher Collins syndrome===

(TCS) A genetic developmental abnormality results from autosomal dominant mutations of the gene TCOF1 encoding the protein Treacle, identified in [http://www.ncbi.nlm.nih.gov/pubmed/8563749 2006]. The syndrome is characterized by hypoplasia of the facial bones, cleft palate, and middle and external ear defects. These defects may relate to the effects on neural crest migration. (More? [[Neural Crest Development]] | [http://www.ncbi.nlm.nih.gov/omim/606847 OMIM - TCOF1] | [http://www.ncbi.nlm.nih.gov/pubmed/8563749 PMID: 8563749])

== References ==
<references/>
===Textbooks===
* '''The Developing Human: Clinically Oriented Embryology''' (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter Chapter 10 The Pharyngeal Apparatus pp201 - 240.
* '''Larsen’s Human Embryology''' by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 12 Development of the Head, the Neck, the Eyes, and the Ears pp349 - 418.

===Online Textbooks===
* '''Developmental Biology''' by Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.section.3109#3133 The Cranial Neural Crest] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3111 Figure 13.1. Regions of the neural crest] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3134 Figure 13.7. Cranial neural crest cell migration in the mammalian head] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3118 Figure 13.2. Neural crest cell migration in the trunk of the chick embryo] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3138 Figure 13.10. Separation of the truncus arteriosus into the pulmonary artery and aorta] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.5460 Figure 22.23. Chick embryo rhombomere neural crest cells and their musculoskeletal packets] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3127 Figure 13.4. Segmental restriction of neural crest cells and motor neurons by the ephrin proteins of the sclerotome] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.43 Figure 1.3. Pharyngeal arches] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.table.3135 Table 13.2. Some derivatives of the pharyngeal arches]

:Neural Crest Experiments: [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.63 Figure 1.11. Neural crest cell migration Chimera experiment] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=dbio.figgrp.3130 Figure 13.5. Pluripotency of trunk neural crest cells]

* '''Molecular Biology of the Cell''' Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=mboc4.figgrp.3946 Figure 21-80. The main pathways of neural crest cell migration] [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=mboc4.figgrp.3968 Figure 21-91. Diagram of a 2-day chick embryo, showing the origins of the nervous system] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=neural_crest&rid=mboc4.figgrp.3511 Figure 19-23. An example of a more complex mechanism by which cells assemble to form a tissue]

* '''Neuroscience''' Purves, Dale; Augustine, George J.; Fitzpatrick, David; Katz, Lawrence C.; LaMantia, Anthony-Samuel; McNamara, James O.; Williams, S. Mark. Sunderland (MA): Sinauer Associates, Inc.; c2001[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=neurosci.figgrp.1449 Figure 22.1. Neurulation in the mammalian embryo] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=neurosci.figgrp.1503 Figure 22.12. Cell signaling during the migration of neural crest cells]
* '''Madame Curie Bioscience Database''' Chapters taken from the Madame Curie Bioscience Database (formerly, Eurekah Bioscience Database) [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A53006 Cranial Neural Crest and Development of the Head Skeleton] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=ch2957 Neural Crest Cells and the Community of Plan for Craniofacial Development: Historical Debates and Current Perspectives] | [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A63004&rendertype=figure&id=A63009 Figure 1. Diagram of an E10 embryo showing the origins of neural crest cells that colonize the developing gastrointestinal tract]

* '''Basic Neurochemistry: Molecular, Cellular, and Medical Aspects''' Siegel, George J.; Agranoff, Bernard W.; Albers, R. Wayne; Fisher, Stephen K.; Uhler, Michael D., editors Philadelphia: Lippincott,Williams & Wilkins; c1999[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?&rid=bnchm.figgrp.1881 Figure 27-10. Neuropoietic model of neural crest cell lineage] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=neural_crest&rid=bnchm.figgrp.1883 Figure 27-11. Growth factor control of neural crest lineage decisions] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=neural_crest&rid=bnchm.figgrp.1893 Figure 27-15. The Schwann cell lineage]

===Search ===

* '''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=neural_crest neural crest]

* '''Pubmed''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=neural_crest neural crest]

== External Links ==
{{External Links}}

* University of Michigan [http://www.biology.lsa.umich.edu/research/labs/ktosney/file/Res/ResNc.html Tosney Lab]
* Stowers Institute [http://www.stowers-institute.org/labs/KulesaLab.asp Kulesa Lab] | [http://www.stowers-institute.org/labs/TrainorLab.asp Trainor Lab]
* University College London [http://www.anat.ucl.ac.uk/research/mayor/index.html Mayor Lab]
* University of Iowa [http://www.anatomy.uiowa.edu/pages/directory/faculty/cornell.asp Cornell Lab]
* Washington University in St. Louis, School of Medicine, Department of Pediatrics [http://peds.wustl.edu/research/labs/Heuckeroth_Robert_O/ Heuckeroth Lab]

{{Glossary}}
{{Footer}}
[[Category:Neural Crest]]

==Reference==
<pubmed>10683170</pubmed>

[[Category:Neural Crest]]

ANAT2341 Lab 5 2013

2013-09-02T05:58:40Z

Z3283213:

=Understanding Mechanisms Using Mouse Models=

==Genetic Background==

One of the major advantages of using mouse models is that they are generally made on an inbred genetic background. This means that all mice are genetically identical except for the genetic modification that is under study. These are referred to as '''congenic mouse lines'''. This lack of genetic variability limits the background variance and allows phenotypic changes to be attributed directly to genotype. The most common mouse line in use is called '''C57BL/6'''

==The test of survival - Mendelian ratios==

Some genetic modifications may threaten the survival of mice during development or cause pre-weaning death due a "failure to thrive".
The average litter size for the C57BL/6 strain is approximately 6
After a few litters it may become apparent that the expected Mendelian ratios are not being met. This can be tested statistically using the Chi Square test.

For example:
A mouse that is hemizygous for a transgene insertion crossed with a wild type mouse would be expected to produce 50% hemizygous transgenic offspring and 50% wild type offspring.
A mouse that has a heterozygous deletion in an endogenous gene crossed with another heterozygous mutant would be expected to produce wild types: heterozygotes amd homozygous mutants at a ratio of 1:2:1

==Examining expression of the gene of interest==
One of the main clues as to where to expect phenotypic consequences is a good knowledge of the expression pattern of the gene of interest. This can be studied from a spatial point of view - i.e. which organs/tissues/cells express the gene of interest, or from a temporal point of view - when does expression begin in these locations (during development?) and when does it cease?

There are several ways of achieving this aim.
#'''Using anti-gene-of-interest antibodies''' on histological tissue sections to determine where the encoded protein is located. This can be technically challenging as it requires a good antibody, abundant levels of protein and good access of the antibody to the location.
#'''RNA In-situ hybridization (ISH)'''. This method is more standardized and predictable but there is still a requirement for reasonably abundant levels of messenger RNA. Several databases are available that curate RNA ISH experiments and most genes in the genome now have at least some data using this technique. [http://www.genepaint.org/Frameset.html GenePaint Website - RNA ISH on sections of developing mouse embryos] [http://www.brain-map.org/ Allen Brain Atlas Website - RNA ISH on sections of mouse brain]
#'''Knock-in of reporter into endogenous gene of interest'''. A common strategy when making a mouse knockout is to also knock-in a recombinant DNA sequence encoding a reporter into the endogenous gene locus. Some examples of reporters that are commonly used include the E.coli LacZ gene, which can be detected using a simple histochemical technique that leaves a blue signal wherever the endogenous gene is normally expressed. GFP - A fluorescent tag based on a jellyfish protein that will glow green when stimulated by UV. Human placental alkaline phosphatase - another histochemical marker.

==Phenotype analysis - Physical==
[http://books.google.com.au/books/about/What_s_Wrong_With_My_Mouse.html?id=uavPtlMY_F4C&redir_esc=y What's Wrong with My Mouse?]

===Body weight===
A simple test that says a lot about impairments in growth and development, is minimally invasive (at postnatal stages) and can be collected throughout the lifespan of the mouse to look at ability to meet growth milestones.

===Histology===
Standard pathological techniques that are used for human subjects are also available here to look for evidence of similar pathology to the human condition. However, in the mouse, there are less ethical restrictions and therefore any tissue can be accessed at any age. Therefore, more detailed analyses can be conducted with larger sample sizes and less genetic background variation.

===Organ/tissue/cell specific tests===
Similarly, with appropriate ethics approval, organs and tissues can be extracted for biochemical analysis, extraction of nucleic acids, proteins, etc
Sometimes cell lines are made from genetically modified mice in order to conduct specific tests in cell culture conditions. For example - mouse embryonic fibroblasts are frequently used for a variety of purposes and keratinocyte cultures are often made from skin samples.

==Phenotype analysis - Developmental==
One of the great advantages of mouse models is the ability to study pathology at any time point throughout development with much less ethical constraint. Tissue can be collected and snap frozen immediately (not during autopsies conducted many hours later) making it feasible to do a variety of different techniques. For example: high quality histology for immunohistochemistry and immunofluorescence or electron microscopy; collection of tissues for protein, RNA or DNA extraction or collection of cells and tissues for cell culture, cell sorting or organ culture.

One main aim is to pinpoint the earliest time point at which things seem to go wrong. Clearly, one would expect things to go wrong in the cell type in which the gene is normally expressed - hence the importance of determining temporal and spatial patterns of expression.

'''Then we can ask questions about why the cells do not behave normally.'''

Do the cells proliferate properly - dysregulation of the cell cycle control machinery? Cancer? e.g. Gorlin syndrome/Basal Cell Nevus Syndrome

''Is there a defect of one of the cell lineages?'' - neural crest derived cells affected in Treacher-Collins and Waardenburg Syndrome type 4

''Is the gene regulating the expression of other genes and if so, what are those gene targets?'' DLX5 in Split-hand/foot malformation is a homeobox gene
T-Box genes - TBX5, TBX1, T, SOX9, PAX6, RUNX2.

''Are cell signalling mechanisms involved?'' - Androgen Receptor (AR) and Endothelin Receptor Type B (ENDRB)

''What is the cellular consequence of loss of gene function?''

''What is the molecular consequence of loss of gene function?''

==Phenotype analysis - Behaviour==
To test functional abilities, a range of test equipment and protocols have been designed to probe functions such as:
#Sensory capabilities - hearing, vision, touch, smell, pain etc
#Motor functions - General motor impulse during the 24hr cycle, motor coordination control, gait and muscle strength
#Learning and memory
#Feeding and drinking
#Reproductive behaviour
#Social behaviour
#Emotional behaviour
#Reward (e.g. self-administration of addictive drugs)

==Molecular analysis==
Once phenotypes have been established and attributed to specific tissues or cell types, it often desirable to probe the molecular cause by conducting biochemical or molecular analyses. This usually involves a direct comparison between protein or nucleic acid samples extracted from the target tissue of a set of genetically modified mice compared with an equal number of samples from control wild-type siblings.

'''Some examples include:'''
#Gene expression profiling using microarray or RNA-seq strategies
#Multiplex protein abundance measurements using 2D gel electrophoresis
#Direct candidate gene expression analysis using quantitative RT-PCR
#Direct candidate protein abundance measurements using Western blotting
#Analysis of pathway activation using markers of protein phosphrylation

=Epigenetics tests=
Recently there has been a dramatic expansion in interest in epigenetic marks as mediators of gene expression control. Therefore, modern molecular strategies often include tests that probe candidate tissues for epigenetic markers such as

#DNA methylation
#Histone methylation
#Histone acetylation
#Nucleosome depletion
#Non-coding RNA

and genes of interest that are involved in transcriptional regulation may involve experiments that are designed to examine direct interaction of the protein under study interacting with target sites on genomic DNA. ChIP (Chromatin immunoprecipitation) techniques.

{{Glossary}}

{{Footer}}

ANAT2341 Lab 5 2013

2013-09-02T05:53:40Z

Z3283213:

=Understanding Mechanisms Using Mouse Models=

==Genetic Background==

One of the major advantages of using mouse models is that they are generally made on an inbred genetic background. This means that all mice are genetically identical except for the genetic modification that is under study. These are referred to as '''congenic mouse lines'''. This lack of genetic variability limits the background variance and allows phenotypic changes to be attributed directly to genotype. The most common mouse line in use is called '''C57BL/6'''

==The test of survival - Mendelian ratios==

Some genetic modifications may threaten the survival of mice during development or cause pre-weaning death due a "failure to thrive".
The average litter size for the C57BL/6 strain is approximately 6
After a few litters it may become apparent that the expected Mendelian ratios are not being met. This can be tested statistically using the Chi Square test.

For example:
A mouse that is hemizygous for a transgene insertion crossed with a wild type mouse would be expected to produce 50% hemizygous transgenic offspring and 50% wild type offspring.
A mouse that has a heterozygous deletion in an endogenous gene crossed with another heterozygous mutant would be expected to produce wild types: heterozygotes amd homozygous mutants at a ratio of 1:2:1

==Examining expression of the gene of interest==
One of the main clues as to where to expect phenotypic consequences is a good knowledge of the expression pattern of the gene of interest. This can be studied from a spatial point of view - i.e. which organs/tissues/cells express the gene of interest, or from a temporal point of view - when does expression begin in these locations (during development?) and when does it cease?
There are several ways of achieving this aim.
#'''Using anti-gene-of-interest antibodies''' on histological tissue sections to determine where the encoded protein is located. This can be technically challenging as it requires a good antibody, abundant levels of protein and good access of the antibody to the location.
#'''RNA In-situ hybridization (ISH)'''. This method is more standardized and predictable but there is still a requirement for reasonably abundant levels of messenger RNA. Several databases are available that curate RNA ISH experiments and most genes in the genome now have at least some data using this technique. [http://www.genepaint.org/Frameset.html GenePaint Website - RNA ISH on sections of developing mouse embryos] [http://www.brain-map.org/ Allen Brain Atlas Website - RNA ISH on sections of mouse brain]
#'''Knock-in of reporter into endogenous gene of interest'''. A common strategy when making a mouse knockout is to also knock-in a recombinant DNA sequence encoding a reporter into the endogenous gene locus. Some examples of reporters that are commonly used include the E.coli LacZ gene, which can be detected using a simple histochemical technique that leaves a blue signal wherever the endogenous gene is normally expressed. GFP - A fluorescent tag based on a jellyfish protein that will glow green when stimulated by UV. Human placental alkaline phosphatase - another histochemical marker.

==Phenotype analysis - Physical==
[http://books.google.com.au/books/about/What_s_Wrong_With_My_Mouse.html?id=uavPtlMY_F4C&redir_esc=y What's Wrong with My Mouse?]

===Body weight===
A simple test that says a lot about impairments in growth and development, is minimally invasive (at postnatal stages) and can be collected throughout the lifespan of the mouse to look at ability to meet growth milestones.

===Histology===
Standard pathological techniques that are used for human subjects are also available here to look for evidence of similar pathology to the human condition. However, in the mouse, there are less ethical restrictions and therefore any tissue can be accessed at any age. Therefore, more detailed analyses can be conducted with larger sample sizes and less genetic background variation.

===Organ/tissue/cell specific tests===
Similarly, with appropriate ethics approval, organs and tissues can be extracted for biochemical analysis, extraction of nucleic acids, proteins, etc
Sometimes cell lines are made from genetically modified mice in order to conduct specific tests in cell culture conditions. For example - mouse embryonic fibroblasts are frequently used for a variety of purposes and keratinocyte cultures are often made from skin samples.

==Phenotype analysis - Developmental==
One of the great advantages of mouse models is the ability to study pathology at any time point throughout development with much less ethical constraint. Tissue can be collected and snap frozen immediately (not during autopsies conducted many hours later) making it feasible to do a variety of different techniques. For example: high quality histology for immunohistochemistry and immunofluorescence or electron microscopy; collection of tissues for protein, RNA or DNA extraction or collection of cells and tissues for cell culture, cell sorting or organ culture.

One main aim is to pinpoint the earliest time point at which things seem to go wrong. Clearly, one would expect things to go wrong in the cell type in which the gene is normally expressed - hence the importance of determining temporal and spatial patterns of expression.

Then we can ask questions about why the cells do not behave normally.

Do the cells proliferate properly - dysregulation of the cell cycle control machinery? Cancer? e.g. Gorlin syndrome/Basal Cell Nevus Syndrome
Is there a defect of one of the cell lineages? - neural crest derived cells affected in Treacher-Collins and Waardenburg Syndrome type 4
Is the gene regulating the expression of other genes and if so, what are those gene targets? DLX5 in Split-hand/foot malformation is a homeobox gene
T-Box genes - TBX5, TBX1, T, SOX9, PAX6, RUNX2.
Cell signalling mechanisms? - Androgen Receptor (AR) and Endothelin Receptor Type B (ENDRB)

What is the cellular consequence of loss of gene function?

==Phenotype analysis - Behaviour==
To test functional abilities, a range of test equipment and protocols have been designed to probe functions such as:
#Sensory capabilities - hearing, vision, touch, smell, pain etc
#Motor functions - General motor impulse during the 24hr cycle, motor coordination control, gait and muscle strength
#Learning and memory
#Feeding and drinking
#Reproductive behaviour
#Social behaviour
#Emotional behaviour
#Reward (e.g. self-administration of addictive drugs)

==Molecular analysis==
Once phenotypes have been established and attributed to specific tissues or cell types, it often desirable to probe the molecular cause by conducting biochemical or molecular analyses. This usually involves a direct comparison between protein or nucleic acid samples extracted from the target tissue of a set of genetically modified mice compared with an equal number of samples from control wild-type siblings.
Some examples include:
#Gene expression profiling using microarray or RNA-seq strategies
#Multiplex protein abundance measurements using 2D gel electrophoresis
#Direct candidate gene expression analysis using quantitative RT-PCR
#Direct candidate protein abundance measurements using Western blotting
#Analysis of pathway activation using markers of protein phosphrylation

=Epigenetics tests=
Recently there has been a dramatic expansion in interest in epigenetic marks as mediators of gene expression control. Therefore, modern molecular strategies often include tests that probe candidate tissues for epigenetic markers such as
#DNA methylation
#Histone methylation
#Histone acetylation
#Nucleosome depletion
#Non-coding RNA

and genes of interest that are involved in transcriptional regulation may involve experiments that are designed to examine direct interaction of the protein under study interacting with target sites on genomic DNA. ChIP (Chromatin immunoprecipitation) techniques.

{{Glossary}}

{{Footer}}

ANAT2341 Lab 5 2013

2013-09-02T03:53:07Z

Z3283213:

=Understanding Mechanisms Using Mouse Models=

==Genetic Background==

One of the major advantages of using mouse models is that they are generally made on an inbred genetic background. This means that all mice are genetically identical except for the genetic modification that is under study. These are referred to as '''congenic mouse lines'''. This lack of genetic variability limits the background variance and allows phenotypic changes to be attributed directly to genotype. The most common mouse line in use is called '''C57BL/6'''

==The test of survival - Mendelian ratios==

Some genetic modifications may threaten the survival of mice during development or cause pre-weaning death due a "failure to thrive".
The average litter size for the C57BL/6 strain is approximately 6
After a few litters it may become apparent that the expected Mendelian ratios are not being met. This can be tested statistically using the Chi Square test.

For example:
A mouse that is hemizygous for a transgene insertion crossed with a wild type mouse would be expected to produce 50% hemizygous transgenic offspring and 50% wild type offspring.
A mouse that has a heterozygous deletion in an endogenous gene crossed with another heterozygous mutant would be expected to produce wild types: heterozygotes amd homozygous mutants at a ratio of 1:2:1

==Examining expression of the gene of interest==
One of the main clues as to where to expect phenotypic consequences is a good knowledge of the expression pattern of the gene of interest. This can be studied from a spatial point of view - i.e. which organs/tissues/cells express the gene of interest, or from a temporal point of view - when does expression begin in these locations (during development?) and when does it cease?
There are several ways of achieving this aim.
#'''Using anti-gene-of-interest antibodies''' on histological tissue sections to determine where the encoded protein is located. This can be technically challenging as it requires a good antibody, abundant levels of protein and good access of the antibody to the location.
#'''RNA In-situ hybridization (ISH)'''. This method is more standardized and predictable but there is still a requirement for reasonably abundant levels of messenger RNA. Several databases are available that curate RNA ISH experiments and most genes in the genome now have at least some data using this technique. [http://www.genepaint.org/Frameset.html GenePaint Website - RNA ISH on sections of developing mouse embryos] [http://www.brain-map.org/ Allen Brain Atlas Website - RNA ISH on sections of mouse brain]
#'''Knock-in of reporter into endogenous gene of interest'''. A common strategy when making a mouse knockout is to also knock-in a recombinant DNA sequence encoding a reporter into the endogenous gene locus. Some examples of reporters that are commonly used include the E.coli LacZ gene, which can be detected using a simple histochemical technique that leaves a blue signal wherever the endogenous gene is normally expressed. GFP - A fluorescent tag based on a jellyfish protein that will glow green when stimulated by UV. Human placental alkaline phosphatase - another histochemical marker.

==Phenotype analysis - Physical==
===Body weight===
A simple test that says a lot about impairments in growth and development, is minimally invasive (at postnatal stages) and can be collected throughout the lifespan of the mouse to look at ability to meet growth milestones.

===Histology===
Standard pathological techniques that are used for human subjects are also available here to look for evidence of similar pathology to the human condition. However, in the mouse, there are less ethical restrictions and therefore any tissue can be accessed at any age. Therefore, more detailed analyses can be conducted with larger sample sizes and less genetic background variation.

===Organ/tissue/cell specific tests===
Similarly, with appropriate ethics approval, organs and tissues can be extracted for biochemical analysis, extraction of nucleic acids, proteins, etc
Sometimes cell lines are made from genetically modified mice in order to conduct specific tests in cell culture conditions. For example - mouse embryonic fibroblasts are frequently used for a variety of purposes and keratinocyte cultures are often made from skin samples.

==Phenotype analysis - Developmental==
One of the great advantages of mouse models is the ability to study pathology at any time point throughout development with much less ethical constraint. Tissue can be collected and snap frozen immediately (not during autopsies conducted many hours later) making it feasible to do a variety of different techniques. For example: high quality histology for immunohistochemistry and immunofluorescence or electron microscopy; collection of tissues for protein, RNA or DNA extraction or collection of cells and tissues for cell culture, cell sorting or organ culture.

One main aim is to pinpoint the earliest time point at which things seem to go wrong.

Then we can ask questions about why the cells do not behave normally.
Do the cells proliferate properly - organized cell cycle control

==Phenotype analysis - Behaviour==
To test functional abilities, a range of test equipment and protocols have been designed to probe functions such as:
#Sensory capabilities - hearing, vision, touch, smell, pain etc
#Motor functions - General motor impulse during the 24hr cycle, motor coordination control, gait and muscle strength
#Learning and memory
#Feeding and drinking
#Reproductive behaviour
#Social behaviour
#Emotional behaviour
#Reward (e.g. self-administration of addictive drugs)

==Molecular analysis==
Once phenotypes have been established and attributed to specific tissues or cell types, it often desirable to probe the molecular cause by conducting biochemical or molecular analyses. This usually involves a direct comparison between protein or nucleic acid samples extracted from the target tissue of a set of genetically modified mice compared with an equal number of samples from control wild-type siblings.
Some examples include:
#Gene expression profiling using microarray or RNA-seq strategies
#Multiplex protein abundance measurements using 2D gel electrophoresis
#Direct candidate gene expression analysis using quantitative RT-PCR
#Direct candidate protein abundance measurements using Western blotting
#Analysis of pathway activation using markers of protein phosphrylation

=Epigenetics tests=
Recently there has been a dramatic expansion in interest in epigenetic marks as mediators of gene expression control. Therefore, modern molecular strategies often include tests that probe candidate tissues for epigenetic markers such as
#DNA methylation
#Histone methylation
#Histone acetylation
#Nucleosome depletion
#Non-coding RNA

and genes of interest that are involved in transcriptional regulation may involve experiments that are designed to examine direct interaction of the protein under study interacting with target sites on genomic DNA. ChIP (Chromatin immunoprecipitation) techniques.

{{Glossary}}

{{Footer}}

Lecture - Respiratory Development

2013-09-02T01:03:36Z

Z3283213:

== Introduction ==
[[File:Gray0971.jpg|thumb|adult lungs]]

The respiratory system does not carry out its physiological function (of gas exchange) until after birth. The respiratory tract, diaphragm and lungs do form early in embryonic development.

The respiratory tract is divided anatomically into 2 main parts:
# '''upper respiratory tract''' - consisting of the nose, nasal cavity and the pharynx.
# '''lower respiratory tract''' - consisting of the larynx, trachea, bronchi and the lungs.

The respiratory "system" usually includes descriptions of not only the functional development of the lungs, but also related musculoskeletal (diaphragm) and vascular (pulmonary) development.

==Lecture Objectives==
[[File:Lung_secondary_lobule_01.jpg|thumb|lung structure]]
[[File:Gray0975.jpg|thumb|alveoli and blood vessels]]
* Understanding of embryonic lung development
* Understanding of the stages of lung development
* Understanding of diaphragm development
* Brief understanding of respiratory vascular development
* Brief understanding of respiratory abnormalities
* Brief understanding of molecular mechanisms

Lecture Date: 2013-09-03 Lecture Time: 16:00 Venue: Biomed E Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Respiratory development 2013.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00008-4&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00008-4 Chapter 8 – Body Cavities and Diaphragm]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00010-2&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00010-2 Chapter 10 – Respiratory System]
|}

===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009.

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10011-9 Chapter 11 - Development of the Respiratory System and Body Cavities]
|}

===UNSW Embryology===
{|
| [[File:Logo.png|90px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.
{{Respiratory Links}}
|}

* '''Anatomy of the Human Body''' 1918 Henry Gray [[Anatomy_of_the_Human_Body_by_Henry_Gray#947_Respiratory|The Respiratory Apparatus]]
* '''Developmental Biology''' 8e Online [http://8e.devbio.com/article.php?ch=15&id=157 Lung Branching Morphogenesis]

==Developmental Overview==
[[File:Stage14 respiratory tract.jpg|thumb|Week 5 Respiratory Development]]

===Lung Development===

* week 4 - 5 embryonic
* week 5 - 17 pseudoglandular
* week 16 - 25 canalicular
* week 24 - 40 terminal sac
* late fetal - 8 years alveolar

===Germ Layers===
* Endoderm and splanchnic mesoderm form majority of conducting and alveoli.
* Ectoderm will contribute the neural innervation.
* Mesoderm also contributes the supporting musculoskeletal components.

===Events===
* '''Week 4''' - laryngotracheal groove forms on floor foregut.
* '''Week 5''' - left and right lung buds push into the pericardioperitoneal canals (primordia of pleural cavity)
* '''Week 6''' - descent of heart and lungs into thorax. Pleuroperitoneal foramen closes.
* '''Week 7''' - enlargement of liver stops descent of heart and lungs.
* '''Month 3-6''' - lungs appear glandular, end month 6 alveolar cells type 2 appear and begin to secrete surfactant.
* '''Month 7''' - respiratory bronchioles proliferate and end in alveolar ducts and sacs.

==Lung Development Stages==
[[File:Lung_alveoli_development_cartoon.jpg|thumb|300px]]
The sequence is most important rather than the actual timing, which is variable in the existing literature.

# week 4 - 5 embryonic
# week 5 - 17 pseudoglandular
# week 16 - 25 canalicular
# week 24 - 40 terminal sac
# late fetal - 8 years alveolar

===Embryonic===
* '''week 4 - 5'''
* Endoderm - tubular ventral growth from foregut pharynx.
* Mesoderm - mesenchyme of lung buds.
* Intraembryonic coelom - pleural cavities elongated spaces connecting pericardial and peritoneal spaces.
===Pseudoglandular stage===
* '''week 5 - 17'''
* tubular branching of the human lung airways continues
* by 2 months all segmental bronchi are present.
* lungs have appearance of a glandlike structure.
* stage is critical for the formation of all conducting airways.
** lined with '''tall columnar epithelium'''
** more distal structures are lined with '''cuboidal epithelium'''.

===Canalicular stage===

* '''week 16 - 24'''
* Lung morphology changes dramatically
* differentiation of the pulmonary epithelium results in the formation of the future air-blood tissue barrier.
* '''Surfactant''' synthesis and the canalization of the lung parenchyma by capillaries begin.
* future gas exchange regions can be distinguished from the future conducting airways of the lungs.

===Saccular stage===
[[File:Alveolar-sac-01.jpg|thumb|Alveolar sac structure]]
* '''week 24 to near term.'''
* most peripheral airways form widened "airspaces", termed saccules.
* saccules widen and lengthen the airspace (by the addition of new generations).
* future gas exchange region expands significantly.
* Fibroblastic cells also undergo differentiation, they produce extracellular matrix, collagen, and elastin.
** May have a role in epithelial differentiation and control of surfactant secretion.
* The vascular tree also grows in length and diameter during this time.

==Foregut development==
[[File:Head arches cartoon.jpg|thumb|Foregut cartoon]]
From the oral cavity the next portion of the foregut is initially a single gastrointestinal (oesophagus) and respiratory (trachea) common tube, the pharynx which lies behind the heart. Note that the respiratory tract will form from a ventral bud arising at this level.

* Oral cavity
* Pharynx (esophagus, trachea)
* Respiratory tract
* Stomach

==Upper respiratory tract==
[[File:Gray0961.jpg|thumb|Adult upper respiratory tract conducting system]]
<gallery>
File:Gitbpm.jpg|stage 11 foregut
File:Gray0982a.jpg|week 4 early respiratory endodermal bud
File:Stage_22_image_167.jpg|Stage 22 trachea
File:Head_arches_cartoon.jpg|Head arches cartoon
File:Pharynx_cartoon.jpg|Pharynx
File:Nasal cavities.jpg|Nasal cavities
File:Pharynx.jpg|Pharynx
File:Larynx.jpg|Larynx
</gallery>
* part of foregut development
* anatomically the nose, nasal cavity and the pharynx
* the pharynx forms a major arched cavity within the pharyngeal arches

'''MH''' - pharyngeal arches will be described in head development lecture

==Lower respiratory tract==
<gallery>
File:Gray0982a.jpg|week 4 early respiratory endodermal bud
File:Gray0982b.jpg|week 4 later ventral endoderm growth
File:Bronchi lungs.jpg|lower respiratory tract
File:Respiratory tract.jpg|conducting system bronchi to lungs
</gallery>
[[File:Lung_development_stage13-22.jpg]] [[File:Stage_22_image_171.jpg|300px]]

[[File:Lung alveoli development cartoon.jpg|thumb|Lung alveoli development cartoon]]
[[File:Fetal lung histology.jpg|thumb|Fetal lung histology]]

* lung buds ( endoderm epithelial tubes) grow/push into mesenchyme covered with pleural cells (lung border)
* generates a tree-like network by repeated:
# elongation
# terminal bifurcation
# lateral budding
* The lungs go through an embryonic and 4 distinct histological phases of development

Growth initially of branched "conducting" system of bronchial tree, followed by later development of the "functional units" of the alveoli.

* '''embryonic''' - week 4 - 5 (stage 14 above)
* '''pseudoglandular''' - week 5 - 17 (stage 22 above)
* '''canalicular''' - week 16 - 25
* '''terminal sac''' - week 24 - 40
* '''alveolar''' - late fetal - 8 years (Latin, ''alveus'' = cavity or hollow)

===Fetal lung volume===
Each human lung volume as determined by ultrasound and matched to gestational age <ref><pubmed>16388511</pubmed></ref>
{|
| Weeks (gestational)
| Volume (ml)
|-
| 12 to 13
| 0.05
|-
| 19 to 22
| 0.5
|-
| 29 to 32
| 1.9
|}

== Pleural Cavity ==
[[File:Gray0965.jpg|thumb|pleura]]
[[File:Gray0968.jpg|thumb|pleura]]
* The anatomical body cavity in which the lungs develop and lie.
* The pleural cavity forms in the lateral plate mesoderm as part of the early single intraembryonic coelom.
* This cavity is initially continuous with pericardial and peritoneal cavities and form initially as two narrow canals
** later becomes separated by folding (pleuropericardial fold, pleuroperitoneal membrane) and the later formation of the diaphragm

pleuropericardial fold - (pleuropericardial membrane) An early embryonic fold which restricts the communication between pleural cavity and pericardiac cavity, contains both the cardinal vein and phrenic nerve.

pleuroperitoneal membrane - An early embryonic membrane that forms inferiorly at the septum transversum to separate peritoneal cavity from pleural cavity.

===Pleura===
* serous membrane covers the surface of the lung and the spaces between the lobes
* arranged as a closed invaginated sac
* two layers (pulmonary, parietal) continuous with each other, the potential space between them is the '''pleural cavity'''

==Diaphragm==
* Not respiratory tract but musculoskeletal development, there are '''5 embryonic elements''' that contribute to the diaphragm.
{|
| [[File:Diaphragm components.jpg|300px|Components of the diaphragm]]
|
# septum transversum- central tendon
# 3rd to 5th somite- musculature of diaphragm
# ventral pleural sac- connective tissue
# mesentry of oesophagus- connective tissue around oesophasus and IVC
# pleuroperitoneal membranes- connective tissue around central tendon
|}
[[File:Gray804.gif|thumb|Adult Cervical Plexus (phrenic nerve shown lower right)]]
[[File:Gray0391.jpg|300px|adult diaphragm]]

* Innervation of the human diaphragm is by the '''phrenic nerves'''
** arising from the same segmental levels from which the diaphragm skeletal muscles arise, segmental levels C3 to C5.
* The paired phrenic nerves are '''mixed nerves'''
** motor neurons for the diaphragm
** sensory nerves for other abdominal structures (mediastinum, pleura, liver, gall bladder).

==Pulmonary Circulation==
[[File:Pulmonary circulation cartoon.jpg|thumb|300px|Pulmonary circulation]]
* the pulmonary system not "functional" until after birth
* pulmonary arteries - 6th aortic arch arteries
* pulmonary veins - are incorporated into the left atrium wall
* bronchial arteries - branches from dorsal aorta

==Fetal==
===Fetal Respiratory Movements===
* Fetal respiratory movements (FRM) or Fetal breathing movements (FBM) are regular muscular contrations occurring in the third trimester.
* thought to be preparing the respiratory muscular system for neonatal function
* thought to also have a role in late lung development.

==The First Breath==
[[File:Alveolar-sac-01.jpg|thumb|Alveolar sac structure]]
* The respiratory system does not carry out its physiological function (gas exchange) prenatally and remain entirely fluid-filled until birth.
* At birth, fluid in the upper respiratory tract is expired and fluid in the lung aveoli is rapidly absorbed this event has also been called "dewatering of the lung".
** The lung epithelia has to now rapidly change from its prenatal secretory function to that of fluid absorbtion.

The exchange of lung fluid for air leads to:
* fall in pulmonary vascular resistance
* increase in pulmonary blood flow
* thinning of pulmonary arteries (stretching as lungs increase in size)
* blood fills the alveolar capillaries

In the heart, pressure in the right side of the heart decreases and pressure in the left side of the heart increases (more blood returning from pulmonary).
[[File:Neonatal rib orientation.jpg|thumb|Rib orientation]]
* Respiratory Rate is higher than adult (30 breaths/minute).

===Rib Orientation===
* Infant rib - is virtually horizontal, allowing diaphragmatic breathing only.
* Adult rib - is oblique (both anterior and lateral views), allows for pump-handle and bucket handle types of inspiration.

== Respiratory Tract Abnormalities ==
[[Respiratory System - Abnormalities]]
===Tracheoesophageal Fistula ===
(Tracheo-Oesophageal Fistula, Oesophageal Atresia) - Oesophageal Atresia with or without tracheo-oesophageal fistula

===Lobar Emphysema (Overinflated Lung)===
# There is an overinflated left upper lobe
# There is a collapsed lower lobe
# The left lung is herniating across the mediastinum

===Congenital Diaphragmatic Hernia===
Failure of the pleuroperitoneal foramen (foramen of Bochdalek) to close allows viscera into thorax. Intestine, stomach or spleen can enter the pleural cavity, compressing the lung.

===Azygos Lobe===
[[File:Lung_Azygos_Lobe_02.jpg|thumb|Lung Azygos Lobe]]
* Common condition (0.5% of population).
* The right lung upper lobe expands either side of the posterior cardinal.
* There is also some course variability of the phrenic nerve in the presence of an azygos lobe.

===Congenital Laryngeal Webs===
* Laryngeal abnormality due to embryonic (week 10) incomplete recanalization of the laryngotracheal tube during the fetal period.
* Rare abnormality occuring mainly at the level of the vocal folds (glottis).

===Meconium Aspiration Syndrome===

* (MAS) Meconium is the gastrointestinal contents that accumulate in the intestines during the fetal period.
* Fetal stress in the third trimester, prior to/at/ or during parturition can lead to premature meconium discharge into the amniotic fluid.
* Subsequent ingestion by the fetus and damage to respiratory function.
* Damage to placental vessels '''meconium myonecrosis''' may also occur.

===Newborn Respiratory Distress Syndrome===
* (Hyaline Membrane Disease) [http://www.nlm.nih.gov/MEDLINEPLUS/ency/article/001563.htm medline plus] | [http://www.medscape.com/article/976034-overview eMedicine]

===Bronchopulmonary Dysplasia===
* A chronic lung disease which can occur following premature birth.
* The definition of bronchopulmonary dysplasia (BPD) has in recent years changed.
* From a severe lung injury and associated repair, to more of a disruption of lung development.

{{Glossary}}
{{Footer}}

[[Category:Endoderm]] [[Category:Respiratory]]

Lecture - Gastrointestinal Development 2013

2013-09-02T01:02:28Z

Z3283213:

=Endoderm Development=
== Introduction ==
[[File:Gray0982a.jpg|thumb|The early developing gastrointestinal tract]]This lecture will cover the early development of the endoderm layer of the trilaminar embryo as it contributes to the lining, glands and organs of the gastrointestinal tract ('''GIT'''). Gastrulation, or gut formation, was historically the easiest observable feature of frog development. In human development, during the 4th week the 3 distinct portions (fore-, mid- and hind-gut) extend the length of the embryo and will contribute different structures. The large mid-gut is generated by lateral embryonic folding which "pinches off" a pocket of the yolk sac, the 2 compartments continue to communicate through the vitelline duct. The oral cavity (mouth) is formed following breakdown of the [[B#buccopharyngeal membrane|buccopharyngeal membrane]] (=oropharyngeal or oral) and the opening means that it contains amniotic fluid, which is also swallowed later in development.

==Lecture Objectives==
[[File:Gray0982b.jpg|thumb|The later developing gastrointestinal tract]]
* Understanding of germ layer contributions to the early gastrointestinal tract (GIT)
* Understanding of the folding of the GIT
* Understanding of three main GIT embryonic divisions
* Understanding of associated organ development (liver, pancreas, spleen)
* Brief understanding of mechanical changes (rotations) during GIT development
* Brief understanding of gastrointestinal abnormalities

Lecture Date: 2013-09-03 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer

The Powerpoint file used to present this lecture is available as a pdf document [[Media:Endoderm Gastrointestinal 2013.pdf‎‎| HERE]]

The audio will be available via the Lectopia system through Blackboard

==Textbooks==

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00011-4&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00011-4 Chapter 11 – Alimentary System]
|}

===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009.

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10014-4 Chapter 14 - Development of the Gastrointestinal Tract]
|}

===UNSW Embryology===
{|
| [[File:Logo.png|90px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.
{{Gastrointestinal Tract Links}}
|}

==Gastrointestinal Tract Movies==

{{GIT_cartoons}}

{| border='0px'
|-
| {{Gastrointestinal stage 13 movie}}
'''Week 4-5''' [[Carnegie stage 13|Stage 13]]
| {{Gastrointestinal stage 22 movie}}
'''Week 8''' [[Carnegie stage 22|Stage 22]]
|}

== Germ Layer Contributions ==

* '''Endoderm''' - epithelium and associated glands.

* '''Mesoderm''' (splanchnic) - mesentry, connective tissues, smooth muscle, blood vessels.

* '''Ectoderm''' (neural crest) - enteric nervous system.

Both endoderm and mesoderm will contribute to associated organs.

==Week 3-4 Folding==
[[File:Stage11 sagittal.jpg|thumb]]
Folding of the embryonic disc occurs ventrally around the notochord, which forms a rod-like region running rostro-caudally in the midline.

In relation to the notochord:

* '''Laterally''' (either side of the notochord) lies mesoderm.
* '''Rostrally''' (above the notochord end) lies the buccopharyngeal membrane, above this again is the mesoderm region forming the heart.
* '''Caudally''' (below the notochord end) lies the primitive streak (where gastrulation occurred), below this again is the cloacal membrane.
* '''Dorsally''' (above the notochord) lies the neural tube then ectoderm.
* '''Ventrally''' (beneath the notochord) lies the mesoderm then endoderm.

The ventral endoderm (shown yellow) has grown to line a space called the yolk sac. Folding of the embryonic disc "pinches off" part of this yolk sac forming the first primative GIT.

{| border='0px'

|-
| [[File:Endoderm_002_icon.jpg|150px|link=Development_Animation_-_Endoderm]]
| [[File:Amnion 001 icon.jpg|150px|link=Development Animation - Amniotic Cavity]]
| [[File:Stage11_sem100.jpg|150px]]
|-
| [[Development_Animation_-_Endoderm|Endoderm]]
| [[Development Animation - Amniotic Cavity|Yolk Sac]]
| Carnegie stage 11 25 days
|}

The cartoon below is a section through the trunk of the trilaminar embryo showing the further development of the 3 layers and the space (coelom) that forms in the mesoderm (only the righhand side is shown).
{|
| [[File:Mesoderm_cartoon4.gif]]
|
* Within the embryonic disc lateral plate mesoderm a space (coelom) forms, it lies within the embryo and so is called the '''intraembryonic coelom'''.
* This single "horseshoe-shaped" space will form the 3 major body cavities: '''pericardial''' (around the heart), '''pleural''' (around the lungs) and '''peritoneal''' (around the GIT and visceral organs).
** The '''intraembryonic coelom''' also communicates with '''extraembryonic coelom''' (space outside the embryo) through portals (holes) initially on lateral margin of embryonic disc.
* The mesoderm adjacennt to the endoderm is now called the '''splanchnic mesoderm''' which forms the connective tissue and muscular wall of the GIT.
|}
===Buccopharyngeal Membrane===
<gallery>
File:Stage11 sem4.jpg|Stage 11 25 days, Low power ventral view of the Buccopharyngeal Membrane
File:Stage11 sem3.jpg|Higher power ventrolateral view of the Buccopharyngeal Membrane
File:Stage11 sem2.jpg|Close up view of the degenerating Buccopharyngeal Membrane
File:Stage12_sem2.jpg|Stage 12 Week 4, 26 days
File:Stage12 sem9 cloacal membrane.jpg|Stage 12 Cloacal membrane
</gallery>

== Week 5-6 Canalization ==
{| border='0px'

|-
| [[File:Gastrointestinal tract growth 01 icon.jpg|150px|link=Development Animation - Gastrointestinal Tract Growth]]
|
* Beginning at week 5 endoderm in the GIT wall proliferates
* Totally blocking (occluding) the lumen by week 6
* Over the next two weeks this tissue degenerates reforming a hollow gut tube.
* The process is called recanalization (hollow, then solid, then hollow again), abnormalities in this process can lead to duplications or stenosis.
* By the end of week 8 the GIT endoderm tube is a tube once more.

|-
| [[Development Animation - Gastrointestinal Tract Growth|Tract Growth]]
|
|}
== Gastrointestinal Tract Divisions ==
{|
|
* During the 4th week the 3 distinct portions (fore-, mid- and hind-gut) extend the length of the embryo and will contribute different components of the GIT.
* These 3 divisions are also later defined by the vascular (artery) supply to each of theses divisions.
* The large '''mid-gut''' is generated by lateral embryonic folding which "pinches off" a pocket of the yolk sac, the 2 compartments continue to communicate through the vitelline duct.
* The '''oral cavity''' ('''mouth''') is formed
** following breakdown of the buccopharyngeal membrane (oropharyngeal, oral membrane)
** contributed to mainly by the pharynx lying within the pharyngeal arches.
** opening of the GIT means that it contains amniotic fluid, which is also swallowed later in development.
| [[File:GIT_blood_supply.jpg|300px]]
|}

===Foregut===
{|
|
* Oral cavity
* Pharynx (esophagus, trachea)
** Respiratory tract (a ventral bud arising at this level, covered in next lecture).
* Stomach
* Duodenum

| [[File:Gitbpm.jpg]]

Stage 11 foregut
|}

===Midgut===

{|
|
* Starting at part of the duodenum, ileum (small intestine), jejunum, and part of the colon (large intestine).
* Much of the '''midgut is herniated''' at the umbilicus external to the abdomen through development. A key step in development is the rotation of this midgut that must occur to place the GIT in the correct abdominal position with its associated mesentry.
* The '''mesentries''' of the GIT are generated from the common '''dorsal mesentry''', with the ventral mesentry contributing to the '''lesser omentum''' and '''falciform ligament'''.

| [[File:Gray0986.jpg|200px]]

midgut herniation
|}

===Hindgut===
* Forms the - distral transverse colon, descending colon, sigmoid colon, rectum and cloaca.
* The '''cloaca''' is the common urogenital sinus which will later become divided (partitioned) into an anterior urogenital and posterior GIT rectal component.

== Stage 13 ==
* The images below provide an overview of the mid-embryonic period (end week 4) [[Carnegie stage 13|stage 13]] embryo gastrointestinal tract.

[[File:Stage14-git.jpg|600px]]

==Stomach==
[[File:Stage14 stomach.jpg|thumb]]
* During week 4 where the stomach will form the GIT tube begins to dilate (forming an enlarged lumen in the tube).
* Dorsal border grows more rapidly than ventral (establishes the greater curvature of the stomach).
* A second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.

[[File:Human Embryo 17.8mm GIT.jpg|400px]]

Stomach, Week 7, Stage 19

:'''Links:''' [[Gastrointestinal Tract - Stomach Development|Stomach Development]]

===Greater Omentum===
[[File:Greater-omentum.jpg|thumb]]
* The greater omentum hangs like an apron over the small intestine and transverse colon.
* It begins attached to the inferior end of the stomach as a fold of the dorsal mesogastrium which later fuses to form the structure we recognise anatomically.
* The figure shows a lateral view of this process comparing the early second trimester arrangement with the newborn structure.

{| border='0px'

|-
| [[File:Greater_omentum_001_icon.jpg|150px|link=Development_Animation_-_Greater_Omentum]]
| [[File:Lesser sac_01_icon.jpg|150px|link=Development_Animation_-_Lesser_Sac]]
|-
| [[Development_Animation_-_Greater_Omentum|Greater Omentum]]
| [[Development_Animation_-_Lesser_Sac|Lesser Sac]]
|-
|}

===Duodenum/Pancreas Rotation===
{|
|
* After the stomach the initial portion of the GIT tube is the duodenum which initially lies in the midline within the peritoneal cavity
* duodenum along with the attached pancreas undergoes rotation
* also incorporated into the body wall to become a retroperitoneal structure.
| [[File:Pancreas_rotation.jpg|300px]]

The diagram shows this rotation with spinal cord at the top, vertebral body then dorsal aorta then pertioneal wall and cavity.
|}

== Midgut ==
* Midgut (intestine) is initially continuous with the yolk sac (externally)
* The connection narrows becoming a "yolk stalk" (and finally lost altogether).
* Initial growth of the midgut forms a loop extending outside the ventral body wall.
* Continued growth occurs outside the body wall (herniated)
* Growth leads to a series of rotates (establishing the adult anatomy)

[[File:Gray0986.jpg|200px|midgut herniation]] [[File:Normal intestinal rotation cartoon.jpg|400px]]

:'''Links:''' [[Gastrointestinal_Tract_-_Intestine_Development|Intestine Development]]

== Gastrointestinal Tract Associated Organs ==

===Liver===
[[File:Stage_22_image_182.jpg|thumb|Liver week 8 stage 22 embryo]]
* The transverse septum (septum transversum) arises at an embryonic junctional site.
** junctional region externally is where the ectoderm of the amnion meets the endoderm of the yolk sac.
** junctional region internally is where the foregut meets the midgut.
* The mesenchymal structure of the transverse septum provides a support within which both blood vessels and the liver begin to form.
** Hepatic Buds - form hepatocytes, produce bile from week 13 (forms meconium of newborn)
** Vitelline Veins - form sinusoids
** Mesenchyme - form connective tissue and Kupffer cells
* Embryonic functions:
** Vascular junction region (placenta, vitelline, systemic)
** Haematopoiesis - location of blood stem cells until bone marrow development.

<gallery>
File:Histology-fetal liver HEx40.jpg|Histology-fetal liver HEx40
File:Histology-fetal_liver_HEx100.jpg|Histology-fetal liver x100
</gallery>
[[File:Liver_structure_cartoon.jpg|thumb|Adult liver structure]]

:'''Links:''' [[Gastrointestinal Tract - Liver Development|Liver Development]]

===Spleen===
[[File:Stage 22 image 087.jpg|thumb|Spleen week 8 stage 22 embryo]]
* Mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas.
* The spleen is located on the left side of the abdomen and has a role initially in blood and then immune system development.
* The spleen's haematopoietic function (blood cell formation) is lost with embryo development and lymphoid precursor cells migrate into the developing organ.
* Vascularization of the spleen arises initially by branches from the dorsal aorta.

{|
| [[File:Lesser sac_01_icon.jpg|200px|link=Development_Animation_-_Lesser_Sac]]
|
'''Legend'''
* '''spleen in mesentery'''
* '''stomach endoderm of gastrointestinal tract'''
* '''liver'''
* '''mesentery'''
|}

:'''Links:''' [[Cardiovascular System - Spleen Development|Spleen Development]]

===Pancreas===
[[File:Stage22 pancreas a.jpg|thumb|Pancreas, week 8 stage 22]]
* At the foregut/midgut junction the septum transversum generates 2 pancreatic buds (dorsal and ventral endoderm) which will fuse to form the pancreas.
* The '''dorsal bud''' arises first and generates most of the pancreas.
* The '''ventral bud''' arises beside the bile duct and forms only part of the head and uncinate process of the pancreas.
* functions - '''exocrine''' and '''endocrine''' (endocrine development will be covered in a later lecture).
[[File:Pancreatic_duct_developing.jpg|300px]] [[File:Mouse-pancreas duct formation.jpg|300px]]

:'''Links:''' [[Gastrointestinal Tract - Pancreas Development|Exocrine Pancreas]] | [[Endocrine - Pancreas Development|Endocrine Pancreas]]

== Gastrointestinal Tract Abnormalities ==
[[File:Meckel%27s_diverticulum_01.jpg|thumb|Meckel's Diverticulum]]
===Lumen Abnormalities===
There are several types of abnormalities that impact upon the continuity of the gastrointestinal tract lumen.

* '''Atresia''' - interuption of the lumen (esophageal atresia, duodenal atresia, extrahepatic biliary atresia, anorectal atresia)
* '''Stenosis''' - narrowing of the lumen (duodenal stenosis, pyloric stenosis).
* '''Duplication''' - incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis.

[[File:Gastrointestinal_tract_duplication_sites.jpg|200px]]

===Meckel's Diverticulum===

* most common gastrointestinal tract abnormality
* results from improper closure and absorption of the omphalomesenteric duct (vitelline duct) in development.
** Transient developmental duct connects the yolk to the primitive GIT.

===Intestinal Malrotation===
[[File:Intestinal_malrotation.jpg|thumb|Intestinal malrotation]]
Presents clinically in symptomatic malrotation as:

* Neonates - bilious vomiting and bloody stools.
* Newborn - bilious vomiting and failure to thrive.
* Infants - recurrent abdominal pain, intestinal obstruction, malabsorption/diarrhea, peritonitis/septic shock, solid food intolerance, common bile duct obstruction, abdominal distention, and failure to thrive.

'''Ladd's Bands''' - are a series of bands crossing the duodenum which can cause duodenal obstruction.

:'''Links:''' [[Gastrointestinal_Tract_-_Abnormalities#Intestinal_Malrotation|Intestinal Malrotation]]

===Intestinal Aganglionosis===

* intestinal aganglionosis, Hirschsprung's disease, aganglionic colon, megacolon, congenital aganglionic megacolon, congenital megacolon
* A condition caused by the lack of enteric nervous system (neural ganglia) in the intestinal tract responsible for gastric motility (peristalsis).

'''MH''' - will cover this topic also in neural crest lecture.

=== Gastroschisis ===
{|
|
* Gastroschisis (omphalocele, paraomphalocele, laparoschisis, abdominoschisis, abdominal hernia)
* congenital abdominal wall defect which results in herniation of fetal abdominal viscera (intestines and/or organs) into the amniotic cavity.
* Incidence of gastroschisis has been reported at 1.66/10,000, occuring more frequently in young mothers (less than 20 years old).
** By definition, it is a body wall defect, not a gastrointestinal tract defect, which in turn impacts upon GIT development.

| [[File:Gastroschisis_01.jpg|150px|link=Ultrasound_-_ Gastroschisis 01]]

:'''Links:''' [[Ultrasound_-_ Gastroschisis 01|Gastroschisis]]
|}

:'''Links:''' [[Gastrointestinal Tract - Abnormalities]]

==Images==
<gallery>

File:Gitbpm.jpg
File:Gray0982a.jpg
File:Gray0982b.jpg
File:Gray0977.jpg
File:Gray0986.jpg
File:Git17mm.jpg
File:Gray0991.jpg
File:Stage14-git.jpg
File:Human_Embryo_17.8mm_GIT.jpg
File:Human_Embryo_17.8mm_a_CNS_GIT.jpg
File:Human_Embryo_17.8mmCNS_GIT.jpg
</gallery>

==UNSW Embryology Links==
{{Template:Gastrointestinal Tract Links}}

==External Links==
{{External Links}}

* '''Embryo Images''' by Drs. Kathleen K. Sulik and Peter R. Bream Jr. notes/images sections on [http://www.med.unc.edu/embryo_images/unit-digest/digest_htms/digesttoc.htm Gut Development]

== Terms ==
'''allantois''' - An extraembryonic membrane, endoderm in origin extension from the early hindgut, then cloaca into the connecting stalk of placental animals, connected to the superior end of developing bladder. In reptiles and birds, acts as a reservoir for wastes and mediates gas exchange. In mammals is associated/incorporated with connecting stalk/placental cord fetal-maternal interface.

'''amnion''' - An extraembryonic membrane]ectoderm and extraembryonic mesoderm in origin and forms the innermost fetal membrane, produces amniotic fluid. This fluid-filled sac initially lies above the trilaminar embryonic disc and with embryoic disc folding this sac is drawn ventrally to enclose (cover) the entire embryo, then fetus. The presence of this membane led to the description of reptiles, bird, and mammals as amniotes.

'''amniotic fluid''' - The fluid that fills amniotic cavity totally encloses and cushions the embryo. Amniotic fluid enters both the gastrointestinal and respiratory tract following rupture of the buccopharyngeal membrane. The late fetus swallows amniotic fluid.

'''buccal''' - (Latin, ''bucca'' = cheek) A term used to relate to the mouth (oral cavity).

'''buccopharyngeal membrane''' - (oral membrane) (Latin, ''bucca'' = cheek) A membrane which forms the external upper membrane limit (cranial end) of the early gastrointestinal tract (GIT). This membrane develops during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm. The membrane lies at the floor of the ventral depression (stomadeum) where the oral cavity will open and will breakdown to form the initial "oral opening" of the gastrointestinal tract. The equivilent membrane at the lower end of the gastrointestinal tract is the cloacal membrane.

'''cloacal membrane''' - Forms the external lower membrane limit (caudal end) of the early gastrointestinal tract (GIT). This membrane is formed during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm. The membrane breaks down to form the initial "anal opening" of the gastrointestinal tract.

'''coelom''' - Term used to describe a space. There are extraembryonic and intraembryonic coeloms that form during vertebrate development. The single intraembryonic coelom will form the 3 major body cavities: pleural, pericardial and peritoneal.

'''foregut''' - The first of the three part/division ('''foregut''' - midgut - hindgut) of the early forming gastrointestinal tract. The foregut runs from the buccopharyngeal membrane to the midgut and forms all the tract (esophagus and stomach) from the oral cavity to beneath the stomach. In addition, a ventral bifurcation of the foregut will also form the respiratory tract epithelium.

'''gastrula''' - (Greek, ''gastrula'' = little stomach) A stage of an animal embryo in which the three germ layers have just formed.

'''gastrulation''' - The process of differentiation forming a gastrula. Term means literally means "to form a gut" but is more in development, as this process converts the bilaminar embryo (epiblast/hypoblast) into the trilaminar embryo ([E.htm#endoderm endoderm]/mesoderm/ectoderm) establishing the 3 germ layers that will form all the future tissues of the entire embryo. This process also establishes the the initial body axes.

'''hindgut''' - The last of the three part/division foregut - midgut - '''hindgut''') of the early forming gastrointestinal tract. The hindgut forms all the tract from the distral transverse colon to the cloacal membrane and extends into the connecting stalk (placental cord) as the allantois. In addition, a ventral of the hindgut will also form the urinary tract (bladder, urethra) epithelium.

'''intraembryonic coelom''' - The "horseshoe-shaped" space (cavity) that forms initially in the third week of development in the lateral plate mesoderm that will eventually form the 3 main body cavities: pericardial, pleural, peritoneal. The intraembryonic coelom communicates transiently with the extraembryonic coelom.

'''neuralation''' - The general term used to describe the early formation of the nervous system. It is often used to describe the early events of differentiation of the central ectoderm region to form the neural plate, then neural groove, then neural tube. The nervous system includes the central nervous system (brain and spinal cord) from the neural tube and the peripheral nervous system (peripheral sensory and sympathetic ganglia) from neural crest. In humans, early neuralation begins in week 3 and continues through week 4.

'''pharynx''' - uppermost end of gastrointestinal and respiratory tract, in the embryo beginning at the buccopharyngeal membrane and forms a major arched cavity within the phrayngeal arches.

'''somitogenesis''' The process of segmentation of the paraxial mesoderm within the trilaminar embryo body to form pairs of somites, or balls of mesoderm. A somite is added either side of the notochord (axial mesoderm) to form a somite pair. The segmentation does not occur in the head region, and begins cranially (head end) and extends caudally (tailward) adding a somite pair at regular time intervals. The process is sequential and therefore used to stage the age of many different species embryos based upon the number visible somite pairs. In humans, the first somite pair appears at day 20 and adds caudally at 1 somite pair/90 minutes until on average 44 pairs eventually form.

'''splanchnic mesoderm''' - Gastrointestinal tract (endoderm) associated mesoderm formed by the separation of the lateral plate mesoderm into two separate components by a cavity, the intraembryonic coelom. Splanchnic mesoderm is the embryonic origin of the gastrointestinal tract connective tissue, smooth muscle, blood vessels and contribute to organ development (pancreas, spleen, liver). The intraembryonic coelom will form the three major body cavities including the space surrounding the gut, the peritoneal cavity. The other half of the lateral plate mesoderm (somatic mesoderm) is associated with the ectoderm of the body wall.

'''stomadeum''' - (stomadeum) A ventral surface depression on the early embryo head surrounding the buccopharyngeal membrane, which lies at the floor of this depression. This surface depression lies between the maxillary and mandibular components of the first pharyngeal arch.

{{Glossary}}

{{Footer}}

[[Category:2012]][[Category:Science-Undergraduate]] [[Category:Gastrointestinal Tract]]

File:Respiratory development 2013.pdf

2013-09-02T01:00:16Z

Z3283213:

File:Endoderm Gastrointestinal 2013.pdf

2013-09-02T00:59:56Z

Z3283213:

Lecture - Respiratory Development

2013-09-01T23:54:55Z

Z3283213:

== Introduction ==
[[File:Gray0971.jpg|thumb|adult lungs]]

The respiratory system does not carry out its physiological function (of gas exchange) until after birth. The respiratory tract, diaphragm and lungs do form early in embryonic development.

The respiratory tract is divided anatomically into 2 main parts:
# '''upper respiratory tract''' - consisting of the nose, nasal cavity and the pharynx.
# '''lower respiratory tract''' - consisting of the larynx, trachea, bronchi and the lungs.

The respiratory "system" usually includes descriptions of not only the functional development of the lungs, but also related musculoskeletal (diaphragm) and vascular (pulmonary) development.

==Lecture Objectives==
[[File:Lung_secondary_lobule_01.jpg|thumb|lung structure]]
[[File:Gray0975.jpg|thumb|alveoli and blood vessels]]
* Understanding of embryonic lung development
* Understanding of the stages of lung development
* Understanding of diaphragm development
* Brief understanding of respiratory vascular development
* Brief understanding of respiratory abnormalities
* Brief understanding of molecular mechanisms

{|

Lecture Date: 2013-09-03 Lecture Time: 16:00 Venue: Biomed E Speaker: Steve Palmer

|}

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00008-4&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00008-4 Chapter 8 – Body Cavities and Diaphragm]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00010-2&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00010-2 Chapter 10 – Respiratory System]
|}

===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009.

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10011-9 Chapter 11 - Development of the Respiratory System and Body Cavities]
|}

===UNSW Embryology===
{|
| [[File:Logo.png|90px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.
{{Respiratory Links}}
|}

* '''Anatomy of the Human Body''' 1918 Henry Gray [[Anatomy_of_the_Human_Body_by_Henry_Gray#947_Respiratory|The Respiratory Apparatus]]
* '''Developmental Biology''' 8e Online [http://8e.devbio.com/article.php?ch=15&id=157 Lung Branching Morphogenesis]

==Developmental Overview==
[[File:Stage14 respiratory tract.jpg|thumb|Week 5 Respiratory Development]]

===Lung Development===

* week 4 - 5 embryonic
* week 5 - 17 pseudoglandular
* week 16 - 25 canalicular
* week 24 - 40 terminal sac
* late fetal - 8 years alveolar

===Germ Layers===
* Endoderm and splanchnic mesoderm form majority of conducting and alveoli.
* Ectoderm will contribute the neural innervation.
* Mesoderm also contributes the supporting musculoskeletal components.

===Events===
* '''Week 4''' - laryngotracheal groove forms on floor foregut.
* '''Week 5''' - left and right lung buds push into the pericardioperitoneal canals (primordia of pleural cavity)
* '''Week 6''' - descent of heart and lungs into thorax. Pleuroperitoneal foramen closes.
* '''Week 7''' - enlargement of liver stops descent of heart and lungs.
* '''Month 3-6''' - lungs appear glandular, end month 6 alveolar cells type 2 appear and begin to secrete surfactant.
* '''Month 7''' - respiratory bronchioles proliferate and end in alveolar ducts and sacs.

==Lung Development Stages==
[[File:Lung_alveoli_development_cartoon.jpg|thumb|300px]]
The sequence is most important rather than the actual timing, which is variable in the existing literature.

# week 4 - 5 embryonic
# week 5 - 17 pseudoglandular
# week 16 - 25 canalicular
# week 24 - 40 terminal sac
# late fetal - 8 years alveolar

===Embryonic===
* '''week 4 - 5'''
* Endoderm - tubular ventral growth from foregut pharynx.
* Mesoderm - mesenchyme of lung buds.
* Intraembryonic coelom - pleural cavities elongated spaces connecting pericardial and peritoneal spaces.
===Pseudoglandular stage===
* '''week 5 - 17'''
* tubular branching of the human lung airways continues
* by 2 months all segmental bronchi are present.
* lungs have appearance of a glandlike structure.
* stage is critical for the formation of all conducting airways.
** lined with '''tall columnar epithelium'''
** more distal structures are lined with '''cuboidal epithelium'''.

===Canalicular stage===

* '''week 16 - 24'''
* Lung morphology changes dramatically
* differentiation of the pulmonary epithelium results in the formation of the future air-blood tissue barrier.
* '''Surfactant''' synthesis and the canalization of the lung parenchyma by capillaries begin.
* future gas exchange regions can be distinguished from the future conducting airways of the lungs.

===Saccular stage===
[[File:Alveolar-sac-01.jpg|thumb|Alveolar sac structure]]
* '''week 24 to near term.'''
* most peripheral airways form widened "airspaces", termed saccules.
* saccules widen and lengthen the airspace (by the addition of new generations).
* future gas exchange region expands significantly.
* Fibroblastic cells also undergo differentiation, they produce extracellular matrix, collagen, and elastin.
** May have a role in epithelial differentiation and control of surfactant secretion.
* The vascular tree also grows in length and diameter during this time.

==Foregut development==
[[File:Head arches cartoon.jpg|thumb|Foregut cartoon]]
From the oral cavity the next portion of the foregut is initially a single gastrointestinal (oesophagus) and respiratory (trachea) common tube, the pharynx which lies behind the heart. Note that the respiratory tract will form from a ventral bud arising at this level.

* Oral cavity
* Pharynx (esophagus, trachea)
* Respiratory tract
* Stomach

==Upper respiratory tract==
[[File:Gray0961.jpg|thumb|Adult upper respiratory tract conducting system]]
<gallery>
File:Gitbpm.jpg|stage 11 foregut
File:Gray0982a.jpg|week 4 early respiratory endodermal bud
File:Stage_22_image_167.jpg|Stage 22 trachea
File:Head_arches_cartoon.jpg|Head arches cartoon
File:Pharynx_cartoon.jpg|Pharynx
File:Nasal cavities.jpg|Nasal cavities
File:Pharynx.jpg|Pharynx
File:Larynx.jpg|Larynx
</gallery>
* part of foregut development
* anatomically the nose, nasal cavity and the pharynx
* the pharynx forms a major arched cavity within the pharyngeal arches

'''MH''' - pharyngeal arches will be described in head development lecture

==Lower respiratory tract==
<gallery>
File:Gray0982a.jpg|week 4 early respiratory endodermal bud
File:Gray0982b.jpg|week 4 later ventral endoderm growth
File:Bronchi lungs.jpg|lower respiratory tract
File:Respiratory tract.jpg|conducting system bronchi to lungs
</gallery>
[[File:Lung_development_stage13-22.jpg]] [[File:Stage_22_image_171.jpg|300px]]

[[File:Lung alveoli development cartoon.jpg|thumb|Lung alveoli development cartoon]]
[[File:Fetal lung histology.jpg|thumb|Fetal lung histology]]

* lung buds ( endoderm epithelial tubes) grow/push into mesenchyme covered with pleural cells (lung border)
* generates a tree-like network by repeated:
# elongation
# terminal bifurcation
# lateral budding
* The lungs go through an embryonic and 4 distinct histological phases of development

Growth initially of branched "conducting" system of bronchial tree, followed by later development of the "functional units" of the alveoli.

* '''embryonic''' - week 4 - 5 (stage 14 above)
* '''pseudoglandular''' - week 5 - 17 (stage 22 above)
* '''canalicular''' - week 16 - 25
* '''terminal sac''' - week 24 - 40
* '''alveolar''' - late fetal - 8 years (Latin, ''alveus'' = cavity or hollow)

===Fetal lung volume===
Each human lung volume as determined by ultrasound and matched to gestational age <ref><pubmed>16388511</pubmed></ref>
{|
| Weeks (gestational)
| Volume (ml)
|-
| 12 to 13
| 0.05
|-
| 19 to 22
| 0.5
|-
| 29 to 32
| 1.9
|}

== Pleural Cavity ==
[[File:Gray0965.jpg|thumb|pleura]]
[[File:Gray0968.jpg|thumb|pleura]]
* The anatomical body cavity in which the lungs develop and lie.
* The pleural cavity forms in the lateral plate mesoderm as part of the early single intraembryonic coelom.
* This cavity is initially continuous with pericardial and peritoneal cavities and form initially as two narrow canals
** later becomes separated by folding (pleuropericardial fold, pleuroperitoneal membrane) and the later formation of the diaphragm

pleuropericardial fold - (pleuropericardial membrane) An early embryonic fold which restricts the communication between pleural cavity and pericardiac cavity, contains both the cardinal vein and phrenic nerve.

pleuroperitoneal membrane - An early embryonic membrane that forms inferiorly at the septum transversum to separate peritoneal cavity from pleural cavity.

===Pleura===
* serous membrane covers the surface of the lung and the spaces between the lobes
* arranged as a closed invaginated sac
* two layers (pulmonary, parietal) continuous with each other, the potential space between them is the '''pleural cavity'''

==Diaphragm==
* Not respiratory tract but musculoskeletal development, there are '''5 embryonic elements''' that contribute to the diaphragm.
{|
| [[File:Diaphragm components.jpg|300px|Components of the diaphragm]]
|
# septum transversum- central tendon
# 3rd to 5th somite- musculature of diaphragm
# ventral pleural sac- connective tissue
# mesentry of oesophagus- connective tissue around oesophasus and IVC
# pleuroperitoneal membranes- connective tissue around central tendon
|}
[[File:Gray804.gif|thumb|Adult Cervical Plexus (phrenic nerve shown lower right)]]
[[File:Gray0391.jpg|300px|adult diaphragm]]

* Innervation of the human diaphragm is by the '''phrenic nerves'''
** arising from the same segmental levels from which the diaphragm skeletal muscles arise, segmental levels C3 to C5.
* The paired phrenic nerves are '''mixed nerves'''
** motor neurons for the diaphragm
** sensory nerves for other abdominal structures (mediastinum, pleura, liver, gall bladder).

==Pulmonary Circulation==
[[File:Pulmonary circulation cartoon.jpg|thumb|300px|Pulmonary circulation]]
* the pulmonary system not "functional" until after birth
* pulmonary arteries - 6th aortic arch arteries
* pulmonary veins - are incorporated into the left atrium wall
* bronchial arteries - branches from dorsal aorta

==Fetal==
===Fetal Respiratory Movements===
* Fetal respiratory movements (FRM) or Fetal breathing movements (FBM) are regular muscular contrations occurring in the third trimester.
* thought to be preparing the respiratory muscular system for neonatal function
* thought to also have a role in late lung development.

==The First Breath==
[[File:Alveolar-sac-01.jpg|thumb|Alveolar sac structure]]
* The respiratory system does not carry out its physiological function (gas exchange) prenatally and remain entirely fluid-filled until birth.
* At birth, fluid in the upper respiratory tract is expired and fluid in the lung aveoli is rapidly absorbed this event has also been called "dewatering of the lung".
** The lung epithelia has to now rapidly change from its prenatal secretory function to that of fluid absorbtion.

The exchange of lung fluid for air leads to:
* fall in pulmonary vascular resistance
* increase in pulmonary blood flow
* thinning of pulmonary arteries (stretching as lungs increase in size)
* blood fills the alveolar capillaries

In the heart, pressure in the right side of the heart decreases and pressure in the left side of the heart increases (more blood returning from pulmonary).
[[File:Neonatal rib orientation.jpg|thumb|Rib orientation]]
* Respiratory Rate is higher than adult (30 breaths/minute).

===Rib Orientation===
* Infant rib - is virtually horizontal, allowing diaphragmatic breathing only.
* Adult rib - is oblique (both anterior and lateral views), allows for pump-handle and bucket handle types of inspiration.

== Respiratory Tract Abnormalities ==
[[Respiratory System - Abnormalities]]
===Tracheoesophageal Fistula ===
(Tracheo-Oesophageal Fistula, Oesophageal Atresia) - Oesophageal Atresia with or without tracheo-oesophageal fistula

===Lobar Emphysema (Overinflated Lung)===
# There is an overinflated left upper lobe
# There is a collapsed lower lobe
# The left lung is herniating across the mediastinum

===Congenital Diaphragmatic Hernia===
Failure of the pleuroperitoneal foramen (foramen of Bochdalek) to close allows viscera into thorax. Intestine, stomach or spleen can enter the pleural cavity, compressing the lung.

===Azygos Lobe===
[[File:Lung_Azygos_Lobe_02.jpg|thumb|Lung Azygos Lobe]]
* Common condition (0.5% of population).
* The right lung upper lobe expands either side of the posterior cardinal.
* There is also some course variability of the phrenic nerve in the presence of an azygos lobe.

===Congenital Laryngeal Webs===
* Laryngeal abnormality due to embryonic (week 10) incomplete recanalization of the laryngotracheal tube during the fetal period.
* Rare abnormality occuring mainly at the level of the vocal folds (glottis).

===Meconium Aspiration Syndrome===

* (MAS) Meconium is the gastrointestinal contents that accumulate in the intestines during the fetal period.
* Fetal stress in the third trimester, prior to/at/ or during parturition can lead to premature meconium discharge into the amniotic fluid.
* Subsequent ingestion by the fetus and damage to respiratory function.
* Damage to placental vessels '''meconium myonecrosis''' may also occur.

===Newborn Respiratory Distress Syndrome===
* (Hyaline Membrane Disease) [http://www.nlm.nih.gov/MEDLINEPLUS/ency/article/001563.htm medline plus] | [http://www.medscape.com/article/976034-overview eMedicine]

===Bronchopulmonary Dysplasia===
* A chronic lung disease which can occur following premature birth.
* The definition of bronchopulmonary dysplasia (BPD) has in recent years changed.
* From a severe lung injury and associated repair, to more of a disruption of lung development.

{{Glossary}}
{{Footer}}

[[Category:Endoderm]] [[Category:Respiratory]]

Lecture - Respiratory Development

2013-08-30T04:08:44Z

Z3283213:

== Introduction ==
[[File:Gray0971.jpg|thumb|adult lungs]]

The respiratory system does not carry out its physiological function (of gas exchange) until after birth. The respiratory tract, diaphragm and lungs do form early in embryonic development.

The respiratory tract is divided anatomically into 2 main parts:
# '''upper respiratory tract''' - consisting of the nose, nasal cavity and the pharynx.
# '''lower respiratory tract''' - consisting of the larynx, trachea, bronchi and the lungs.

The respiratory "system" usually includes descriptions of not only the functional development of the lungs, but also related musculoskeletal (diaphragm) and vascular (pulmonary) development.

'''Links:''' [[Respiratory System Development]] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development&oldid=101050 2012 Lecture]

==Lecture Objectives==
[[File:Lung_secondary_lobule_01.jpg|thumb|lung structure]]
[[File:Gray0975.jpg|thumb|alveoli and blood vessels]]
* Understanding of embryonic lung development
* Understanding of the stages of lung development
* Understanding of diaphragm development
* Brief understanding of respiratory vascular development
* Brief understanding of respiratory abnormalities
* Brief understanding of molecular mechanisms

{|

Lecture Date: 2013-09-03 Lecture Time: 16:00 Venue: Biomed E Speaker: Steve Palmer

|}

==Textbooks==
===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00008-4&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00008-4 Chapter 8 – Body Cavities and Diaphragm]
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00010-2&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00010-2 Chapter 10 – Respiratory System]
|}

===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009.

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10011-9 Chapter 11 - Development of the Respiratory System and Body Cavities]
|}

===UNSW Embryology===
{|
| [[File:Logo.png|90px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.
{{Respiratory Links}}
|}

* '''Anatomy of the Human Body''' 1918 Henry Gray [[Anatomy_of_the_Human_Body_by_Henry_Gray#947_Respiratory|The Respiratory Apparatus]]
* '''Developmental Biology''' 8e Online [http://8e.devbio.com/article.php?ch=15&id=157 Lung Branching Morphogenesis]

==Developmental Overview==
[[File:Stage14 respiratory tract.jpg|thumb|Week 5 Respiratory Development]]

===Lung Development===

* week 4 - 5 embryonic
* week 5 - 17 pseudoglandular
* week 16 - 25 canalicular
* week 24 - 40 terminal sac
* late fetal - 8 years alveolar

===Germ Layers===
* Endoderm and splanchnic mesoderm form majority of conducting and alveoli.
* Ectoderm will contribute the neural innervation.
* Mesoderm also contributes the supporting musculoskeletal components.

===Events===
* '''Week 4''' - laryngotracheal groove forms on floor foregut.
* '''Week 5''' - left and right lung buds push into the pericardioperitoneal canals (primordia of pleural cavity)
* '''Week 6''' - descent of heart and lungs into thorax. Pleuroperitoneal foramen closes.
* '''Week 7''' - enlargement of liver stops descent of heart and lungs.
* '''Month 3-6''' - lungs appear glandular, end month 6 alveolar cells type 2 appear and begin to secrete surfactant.
* '''Month 7''' - respiratory bronchioles proliferate and end in alveolar ducts and sacs.

==Lung Development Stages==
[[File:Lung_alveoli_development_cartoon.jpg|thumb|300px]]
The sequence is most important rather than the actual timing, which is variable in the existing literature.

# week 4 - 5 embryonic
# week 5 - 17 pseudoglandular
# week 16 - 25 canalicular
# week 24 - 40 terminal sac
# late fetal - 8 years alveolar

===Embryonic===
* '''week 4 - 5'''
* Endoderm - tubular ventral growth from foregut pharynx.
* Mesoderm - mesenchyme of lung buds.
* Intraembryonic coelom - pleural cavities elongated spaces connecting pericardial and peritoneal spaces.
===Pseudoglandular stage===
* '''week 5 - 17'''
* tubular branching of the human lung airways continues
* by 2 months all segmental bronchi are present.
* lungs have appearance of a glandlike structure.
* stage is critical for the formation of all conducting airways.
** lined with '''tall columnar epithelium'''
** more distal structures are lined with '''cuboidal epithelium'''.

===Canalicular stage===

* '''week 16 - 24'''
* Lung morphology changes dramatically
* differentiation of the pulmonary epithelium results in the formation of the future air-blood tissue barrier.
* '''Surfactant''' synthesis and the canalization of the lung parenchyma by capillaries begin.
* future gas exchange regions can be distinguished from the future conducting airways of the lungs.

===Saccular stage===
[[File:Alveolar-sac-01.jpg|thumb|Alveolar sac structure]]
* '''week 24 to near term.'''
* most peripheral airways form widened "airspaces", termed saccules.
* saccules widen and lengthen the airspace (by the addition of new generations).
* future gas exchange region expands significantly.
* Fibroblastic cells also undergo differentiation, they produce extracellular matrix, collagen, and elastin.
** May have a role in epithelial differentiation and control of surfactant secretion.
* The vascular tree also grows in length and diameter during this time.

==Foregut development==
[[File:Head arches cartoon.jpg|thumb|Foregut cartoon]]
From the oral cavity the next portion of the foregut is initially a single gastrointestinal (oesophagus) and respiratory (trachea) common tube, the pharynx which lies behind the heart. Note that the respiratory tract will form from a ventral bud arising at this level.

* Oral cavity
* Pharynx (esophagus, trachea)
* Respiratory tract
* Stomach

==Upper respiratory tract==
[[File:Gray0961.jpg|thumb|Adult upper respiratory tract conducting system]]
<gallery>
File:Gitbpm.jpg|stage 11 foregut
File:Gray0982a.jpg|week 4 early respiratory endodermal bud
File:Stage_22_image_167.jpg|Stage 22 trachea
File:Head_arches_cartoon.jpg|Head arches cartoon
File:Pharynx_cartoon.jpg|Pharynx
File:Nasal cavities.jpg|Nasal cavities
File:Pharynx.jpg|Pharynx
File:Larynx.jpg|Larynx
</gallery>
* part of foregut development
* anatomically the nose, nasal cavity and the pharynx
* the pharynx forms a major arched cavity within the pharyngeal arches

'''MH''' - pharyngeal arches will be described in head development lecture

==Lower respiratory tract==
<gallery>
File:Gray0982a.jpg|week 4 early respiratory endodermal bud
File:Gray0982b.jpg|week 4 later ventral endoderm growth
File:Bronchi lungs.jpg|lower respiratory tract
File:Respiratory tract.jpg|conducting system bronchi to lungs
</gallery>
[[File:Lung_development_stage13-22.jpg]] [[File:Stage_22_image_171.jpg|300px]]

[[File:Lung alveoli development cartoon.jpg|thumb|Lung alveoli development cartoon]]
[[File:Fetal lung histology.jpg|thumb|Fetal lung histology]]

* lung buds ( endoderm epithelial tubes) grow/push into mesenchyme covered with pleural cells (lung border)
* generates a tree-like network by repeated:
# elongation
# terminal bifurcation
# lateral budding
* The lungs go through an embryonic and 4 distinct histological phases of development

Growth initially of branched "conducting" system of bronchial tree, followed by later development of the "functional units" of the alveoli.

* '''embryonic''' - week 4 - 5 (stage 14 above)
* '''pseudoglandular''' - week 5 - 17 (stage 22 above)
* '''canalicular''' - week 16 - 25
* '''terminal sac''' - week 24 - 40
* '''alveolar''' - late fetal - 8 years (Latin, ''alveus'' = cavity or hollow)

===Fetal lung volume===
Each human lung volume as determined by ultrasound and matched to gestational age <ref><pubmed>16388511</pubmed></ref>
{|
| Weeks (gestational)
| Volume (ml)
|-
| 12 to 13
| 0.05
|-
| 19 to 22
| 0.5
|-
| 29 to 32
| 1.9
|}

== Pleural Cavity ==
[[File:Gray0965.jpg|thumb|pleura]]
[[File:Gray0968.jpg|thumb|pleura]]
* The anatomical body cavity in which the lungs develop and lie.
* The pleural cavity forms in the lateral plate mesoderm as part of the early single intraembryonic coelom.
* This cavity is initially continuous with pericardial and peritoneal cavities and form initially as two narrow canals
** later becomes separated by folding (pleuropericardial fold, pleuroperitoneal membrane) and the later formation of the diaphragm

pleuropericardial fold - (pleuropericardial membrane) An early embryonic fold which restricts the communication between pleural cavity and pericardiac cavity, contains both the cardinal vein and phrenic nerve.

pleuroperitoneal membrane - An early embryonic membrane that forms inferiorly at the septum transversum to separate peritoneal cavity from pleural cavity.

===Pleura===
* serous membrane covers the surface of the lung and the spaces between the lobes
* arranged as a closed invaginated sac
* two layers (pulmonary, parietal) continuous with each other, the potential space between them is the '''pleural cavity'''

==Diaphragm==
* Not respiratory tract but musculoskeletal development, there are '''5 embryonic elements''' that contribute to the diaphragm.
{|
| [[File:Diaphragm components.jpg|300px|Components of the diaphragm]]
|
# septum transversum- central tendon
# 3rd to 5th somite- musculature of diaphragm
# ventral pleural sac- connective tissue
# mesentry of oesophagus- connective tissue around oesophasus and IVC
# pleuroperitoneal membranes- connective tissue around central tendon
|}
[[File:Gray804.gif|thumb|Adult Cervical Plexus (phrenic nerve shown lower right)]]
[[File:Gray0391.jpg|300px|adult diaphragm]]

* Innervation of the human diaphragm is by the '''phrenic nerves'''
** arising from the same segmental levels from which the diaphragm skeletal muscles arise, segmental levels C3 to C5.
* The paired phrenic nerves are '''mixed nerves'''
** motor neurons for the diaphragm
** sensory nerves for other abdominal structures (mediastinum, pleura, liver, gall bladder).

==Pulmonary Circulation==
[[File:Pulmonary circulation cartoon.jpg|thumb|300px|Pulmonary circulation]]
* the pulmonary system not "functional" until after birth
* pulmonary arteries - 6th aortic arch arteries
* pulmonary veins - are incorporated into the left atrium wall
* bronchial arteries - branches from dorsal aorta

==Fetal==
===Fetal Respiratory Movements===
* Fetal respiratory movements (FRM) or Fetal breathing movements (FBM) are regular muscular contrations occurring in the third trimester.
* thought to be preparing the respiratory muscular system for neonatal function
* thought to also have a role in late lung development.

==The First Breath==
[[File:Alveolar-sac-01.jpg|thumb|Alveolar sac structure]]
* The respiratory system does not carry out its physiological function (gas exchange) prenatally and remain entirely fluid-filled until birth.
* At birth, fluid in the upper respiratory tract is expired and fluid in the lung aveoli is rapidly absorbed this event has also been called "dewatering of the lung".
** The lung epithelia has to now rapidly change from its prenatal secretory function to that of fluid absorbtion.

The exchange of lung fluid for air leads to:
* fall in pulmonary vascular resistance
* increase in pulmonary blood flow
* thinning of pulmonary arteries (stretching as lungs increase in size)
* blood fills the alveolar capillaries

In the heart, pressure in the right side of the heart decreases and pressure in the left side of the heart increases (more blood returning from pulmonary).
[[File:Neonatal rib orientation.jpg|thumb|Rib orientation]]
* Respiratory Rate is higher than adult (30 breaths/minute).

===Rib Orientation===
* Infant rib - is virtually horizontal, allowing diaphragmatic breathing only.
* Adult rib - is oblique (both anterior and lateral views), allows for pump-handle and bucket handle types of inspiration.

== Respiratory Tract Abnormalities ==
[[Respiratory System - Abnormalities]]
===Tracheoesophageal Fistula ===
(Tracheo-Oesophageal Fistula, Oesophageal Atresia) - Oesophageal Atresia with or without tracheo-oesophageal fistula

===Lobar Emphysema (Overinflated Lung)===
# There is an overinflated left upper lobe
# There is a collapsed lower lobe
# The left lung is herniating across the mediastinum

===Congenital Diaphragmatic Hernia===
Failure of the pleuroperitoneal foramen (foramen of Bochdalek) to close allows viscera into thorax. Intestine, stomach or spleen can enter the pleural cavity, compressing the lung.

===Azygos Lobe===
[[File:Lung_Azygos_Lobe_02.jpg|thumb|Lung Azygos Lobe]]
* Common condition (0.5% of population).
* The right lung upper lobe expands either side of the posterior cardinal.
* There is also some course variability of the phrenic nerve in the presence of an azygos lobe.

===Congenital Laryngeal Webs===
* Laryngeal abnormality due to embryonic (week 10) incomplete recanalization of the laryngotracheal tube during the fetal period.
* Rare abnormality occuring mainly at the level of the vocal folds (glottis).

===Meconium Aspiration Syndrome===

* (MAS) Meconium is the gastrointestinal contents that accumulate in the intestines during the fetal period.
* Fetal stress in the third trimester, prior to/at/ or during parturition can lead to premature meconium discharge into the amniotic fluid.
* Subsequent ingestion by the fetus and damage to respiratory function.
* Damage to placental vessels '''meconium myonecrosis''' may also occur.

===Newborn Respiratory Distress Syndrome===
* (Hyaline Membrane Disease) [http://www.nlm.nih.gov/MEDLINEPLUS/ency/article/001563.htm medline plus] | [http://www.medscape.com/article/976034-overview eMedicine]

===Bronchopulmonary Dysplasia===
* A chronic lung disease which can occur following premature birth.
* The definition of bronchopulmonary dysplasia (BPD) has in recent years changed.
* From a severe lung injury and associated repair, to more of a disruption of lung development.

{{Glossary}}
{{Footer}}

[[Category:Endoderm]] [[Category:Respiratory]]

Lecture - Gastrointestinal Development 2013

2013-08-29T05:52:17Z

Z3283213:

=Endoderm Development=
== Introduction ==
[[File:Gray0982a.jpg|thumb|The early developing gastrointestinal tract]]This lecture will cover the early development of the endoderm layer of the trilaminar embryo as it contributes to the lining, glands and organs of the gastrointestinal tract ('''GIT'''). Gastrulation, or gut formation, was historically the easiest observable feature of frog development. In human development, during the 4th week the 3 distinct portions (fore-, mid- and hind-gut) extend the length of the embryo and will contribute different structures. The large mid-gut is generated by lateral embryonic folding which "pinches off" a pocket of the yolk sac, the 2 compartments continue to communicate through the vitelline duct. The oral cavity (mouth) is formed following breakdown of the [[B#buccopharyngeal membrane|buccopharyngeal membrane]] (=oropharyngeal or oral) and the opening means that it contains amniotic fluid, which is also swallowed later in development.

==Lecture Objectives==
[[File:Gray0982b.jpg|thumb|The later developing gastrointestinal tract]]
* Understanding of germ layer contributions to the early gastrointestinal tract (GIT)
* Understanding of the folding of the GIT
* Understanding of three main GIT embryonic divisions
* Understanding of associated organ development (liver, pancreas, spleen)
* Brief understanding of mechanical changes (rotations) during GIT development
* Brief understanding of gastrointestinal abnormalities

{|
Lecture Date: 2013-09-03 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer
|}

==Textbooks==

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00011-4&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00011-4 Chapter 11 – Alimentary System]
|}

===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009.

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10014-4 Chapter 14 - Development of the Gastrointestinal Tract]
|}

===UNSW Embryology===
{|
| [[File:Logo.png|90px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.
{{Gastrointestinal Tract Links}}
|}

==Gastrointestinal Tract Movies==

{{GIT_cartoons}}

{| border='0px'
|-
| {{Gastrointestinal stage 13 movie}}
'''Week 4-5''' [[Carnegie stage 13|Stage 13]]
| {{Gastrointestinal stage 22 movie}}
'''Week 8''' [[Carnegie stage 22|Stage 22]]
|}

== Germ Layer Contributions ==

* '''Endoderm''' - epithelium and associated glands.

* '''Mesoderm''' (splanchnic) - mesentry, connective tissues, smooth muscle, blood vessels.

* '''Ectoderm''' (neural crest) - enteric nervous system.

Both endoderm and mesoderm will contribute to associated organs.

==Week 3-4 Folding==
[[File:Stage11 sagittal.jpg|thumb]]
Folding of the embryonic disc occurs ventrally around the notochord, which forms a rod-like region running rostro-caudally in the midline.

In relation to the notochord:

* '''Laterally''' (either side of the notochord) lies mesoderm.
* '''Rostrally''' (above the notochord end) lies the buccopharyngeal membrane, above this again is the mesoderm region forming the heart.
* '''Caudally''' (below the notochord end) lies the primitive streak (where gastrulation occurred), below this again is the cloacal membrane.
* '''Dorsally''' (above the notochord) lies the neural tube then ectoderm.
* '''Ventrally''' (beneath the notochord) lies the mesoderm then endoderm.

The ventral endoderm (shown yellow) has grown to line a space called the yolk sac. Folding of the embryonic disc "pinches off" part of this yolk sac forming the first primative GIT.

{| border='0px'

|-
| [[File:Endoderm_002_icon.jpg|150px|link=Development_Animation_-_Endoderm]]
| [[File:Amnion 001 icon.jpg|150px|link=Development Animation - Amniotic Cavity]]
| [[File:Stage11_sem100.jpg|150px]]
|-
| [[Development_Animation_-_Endoderm|Endoderm]]
| [[Development Animation - Amniotic Cavity|Yolk Sac]]
| Carnegie stage 11 25 days
|}

The cartoon below is a section through the trunk of the trilaminar embryo showing the further development of the 3 layers and the space (coelom) that forms in the mesoderm (only the righhand side is shown).
{|
| [[File:Mesoderm_cartoon4.gif]]
|
* Within the embryonic disc lateral plate mesoderm a space (coelom) forms, it lies within the embryo and so is called the '''intraembryonic coelom'''.
* This single "horseshoe-shaped" space will form the 3 major body cavities: '''pericardial''' (around the heart), '''pleural''' (around the lungs) and '''peritoneal''' (around the GIT and visceral organs).
** The '''intraembryonic coelom''' also communicates with '''extraembryonic coelom''' (space outside the embryo) through portals (holes) initially on lateral margin of embryonic disc.
* The mesoderm adjacennt to the endoderm is now called the '''splanchnic mesoderm''' which forms the connective tissue and muscular wall of the GIT.
|}
===Buccopharyngeal Membrane===
<gallery>
File:Stage11 sem4.jpg|Stage 11 25 days, Low power ventral view of the Buccopharyngeal Membrane
File:Stage11 sem3.jpg|Higher power ventrolateral view of the Buccopharyngeal Membrane
File:Stage11 sem2.jpg|Close up view of the degenerating Buccopharyngeal Membrane
File:Stage12_sem2.jpg|Stage 12 Week 4, 26 days
File:Stage12 sem9 cloacal membrane.jpg|Stage 12 Cloacal membrane
</gallery>

== Week 5-6 Canalization ==
{| border='0px'

|-
| [[File:Gastrointestinal tract growth 01 icon.jpg|150px|link=Development Animation - Gastrointestinal Tract Growth]]
|
* Beginning at week 5 endoderm in the GIT wall proliferates
* Totally blocking (occluding) the lumen by week 6
* Over the next two weeks this tissue degenerates reforming a hollow gut tube.
* The process is called recanalization (hollow, then solid, then hollow again), abnormalities in this process can lead to duplications or stenosis.
* By the end of week 8 the GIT endoderm tube is a tube once more.

|-
| [[Development Animation - Gastrointestinal Tract Growth|Tract Growth]]
|
|}
== Gastrointestinal Tract Divisions ==
{|
|
* During the 4th week the 3 distinct portions (fore-, mid- and hind-gut) extend the length of the embryo and will contribute different components of the GIT.
* These 3 divisions are also later defined by the vascular (artery) supply to each of theses divisions.
* The large '''mid-gut''' is generated by lateral embryonic folding which "pinches off" a pocket of the yolk sac, the 2 compartments continue to communicate through the vitelline duct.
* The '''oral cavity''' ('''mouth''') is formed
** following breakdown of the buccopharyngeal membrane (oropharyngeal, oral membrane)
** contributed to mainly by the pharynx lying within the pharyngeal arches.
** opening of the GIT means that it contains amniotic fluid, which is also swallowed later in development.
| [[File:GIT_blood_supply.jpg|300px]]
|}

===Foregut===
{|
|
* Oral cavity
* Pharynx (esophagus, trachea)
** Respiratory tract (a ventral bud arising at this level, covered in next lecture).
* Stomach
* Duodenum

| [[File:Gitbpm.jpg]]

Stage 11 foregut
|}

===Midgut===

{|
|
* Starting at part of the duodenum, ileum (small intestine), jejunum, and part of the colon (large intestine).
* Much of the '''midgut is herniated''' at the umbilicus external to the abdomen through development. A key step in development is the rotation of this midgut that must occur to place the GIT in the correct abdominal position with its associated mesentry.
* The '''mesentries''' of the GIT are generated from the common '''dorsal mesentry''', with the ventral mesentry contributing to the '''lesser omentum''' and '''falciform ligament'''.

| [[File:Gray0986.jpg|200px]]

midgut herniation
|}

===Hindgut===
* Forms the - distral transverse colon, descending colon, sigmoid colon, rectum and cloaca.
* The '''cloaca''' is the common urogenital sinus which will later become divided (partitioned) into an anterior urogenital and posterior GIT rectal component.

== Stage 13 ==
* The images below provide an overview of the mid-embryonic period (end week 4) [[Carnegie stage 13|stage 13]] embryo gastrointestinal tract.

[[File:Stage14-git.jpg|600px]]

==Stomach==
[[File:Stage14 stomach.jpg|thumb]]
* During week 4 where the stomach will form the GIT tube begins to dilate (forming an enlarged lumen in the tube).
* Dorsal border grows more rapidly than ventral (establishes the greater curvature of the stomach).
* A second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.

[[File:Human Embryo 17.8mm GIT.jpg|400px]]

Stomach, Week 7, Stage 19

:'''Links:''' [[Gastrointestinal Tract - Stomach Development|Stomach Development]]

===Greater Omentum===
[[File:Greater-omentum.jpg|thumb]]
* The greater omentum hangs like an apron over the small intestine and transverse colon.
* It begins attached to the inferior end of the stomach as a fold of the dorsal mesogastrium which later fuses to form the structure we recognise anatomically.
* The figure shows a lateral view of this process comparing the early second trimester arrangement with the newborn structure.

{| border='0px'

|-
| [[File:Greater_omentum_001_icon.jpg|150px|link=Development_Animation_-_Greater_Omentum]]
| [[File:Lesser sac_01_icon.jpg|150px|link=Development_Animation_-_Lesser_Sac]]
|-
| [[Development_Animation_-_Greater_Omentum|Greater Omentum]]
| [[Development_Animation_-_Lesser_Sac|Lesser Sac]]
|-
|}

===Duodenum/Pancreas Rotation===
{|
|
* After the stomach the initial portion of the GIT tube is the duodenum which initially lies in the midline within the peritoneal cavity
* duodenum along with the attached pancreas undergoes rotation
* also incorporated into the body wall to become a retroperitoneal structure.
| [[File:Pancreas_rotation.jpg|300px]]

The diagram shows this rotation with spinal cord at the top, vertebral body then dorsal aorta then pertioneal wall and cavity.
|}

== Midgut ==
* Midgut (intestine) is initially continuous with the yolk sac (externally)
* The connection narrows becoming a "yolk stalk" (and finally lost altogether).
* Initial growth of the midgut forms a loop extending outside the ventral body wall.
* Continued growth occurs outside the body wall (herniated)
* Growth leads to a series of rotates (establishing the adult anatomy)

[[File:Gray0986.jpg|200px|midgut herniation]] [[File:Normal intestinal rotation cartoon.jpg|400px]]

:'''Links:''' [[Gastrointestinal_Tract_-_Intestine_Development|Intestine Development]]

== Gastrointestinal Tract Associated Organs ==

===Liver===
[[File:Stage_22_image_182.jpg|thumb|Liver week 8 stage 22 embryo]]
* The transverse septum (septum transversum) arises at an embryonic junctional site.
** junctional region externally is where the ectoderm of the amnion meets the endoderm of the yolk sac.
** junctional region internally is where the foregut meets the midgut.
* The mesenchymal structure of the transverse septum provides a support within which both blood vessels and the liver begin to form.
** Hepatic Buds - form hepatocytes, produce bile from week 13 (forms meconium of newborn)
** Vitelline Veins - form sinusoids
** Mesenchyme - form connective tissue and Kupffer cells
* Embryonic functions:
** Vascular junction region (placenta, vitelline, systemic)
** Haematopoiesis - location of blood stem cells until bone marrow development.

<gallery>
File:Histology-fetal liver HEx40.jpg|Histology-fetal liver HEx40
File:Histology-fetal_liver_HEx100.jpg|Histology-fetal liver x100
</gallery>
[[File:Liver_structure_cartoon.jpg|thumb|Adult liver structure]]

:'''Links:''' [[Gastrointestinal Tract - Liver Development|Liver Development]]

===Spleen===
[[File:Stage 22 image 087.jpg|thumb|Spleen week 8 stage 22 embryo]]
* Mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas.
* The spleen is located on the left side of the abdomen and has a role initially in blood and then immune system development.
* The spleen's haematopoietic function (blood cell formation) is lost with embryo development and lymphoid precursor cells migrate into the developing organ.
* Vascularization of the spleen arises initially by branches from the dorsal aorta.

{|
| [[File:Lesser sac_01_icon.jpg|200px|link=Development_Animation_-_Lesser_Sac]]
|
'''Legend'''
* '''spleen in mesentery'''
* '''stomach endoderm of gastrointestinal tract'''
* '''liver'''
* '''mesentery'''
|}

:'''Links:''' [[Cardiovascular System - Spleen Development|Spleen Development]]

===Pancreas===
[[File:Stage22 pancreas a.jpg|thumb|Pancreas, week 8 stage 22]]
* At the foregut/midgut junction the septum transversum generates 2 pancreatic buds (dorsal and ventral endoderm) which will fuse to form the pancreas.
* The '''dorsal bud''' arises first and generates most of the pancreas.
* The '''ventral bud''' arises beside the bile duct and forms only part of the head and uncinate process of the pancreas.
* functions - '''exocrine''' and '''endocrine''' (endocrine development will be covered in a later lecture).
[[File:Pancreatic_duct_developing.jpg|300px]] [[File:Mouse-pancreas duct formation.jpg|300px]]

:'''Links:''' [[Gastrointestinal Tract - Pancreas Development|Exocrine Pancreas]] | [[Endocrine - Pancreas Development|Endocrine Pancreas]]

== Gastrointestinal Tract Abnormalities ==
[[File:Meckel%27s_diverticulum_01.jpg|thumb|Meckel's Diverticulum]]
===Lumen Abnormalities===
There are several types of abnormalities that impact upon the continuity of the gastrointestinal tract lumen.

* '''Atresia''' - interuption of the lumen (esophageal atresia, duodenal atresia, extrahepatic biliary atresia, anorectal atresia)
* '''Stenosis''' - narrowing of the lumen (duodenal stenosis, pyloric stenosis).
* '''Duplication''' - incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis.

[[File:Gastrointestinal_tract_duplication_sites.jpg|200px]]

===Meckel's Diverticulum===

* most common gastrointestinal tract abnormality
* results from improper closure and absorption of the omphalomesenteric duct (vitelline duct) in development.
** Transient developmental duct connects the yolk to the primitive GIT.

===Intestinal Malrotation===
[[File:Intestinal_malrotation.jpg|thumb|Intestinal malrotation]]
Presents clinically in symptomatic malrotation as:

* Neonates - bilious vomiting and bloody stools.
* Newborn - bilious vomiting and failure to thrive.
* Infants - recurrent abdominal pain, intestinal obstruction, malabsorption/diarrhea, peritonitis/septic shock, solid food intolerance, common bile duct obstruction, abdominal distention, and failure to thrive.

'''Ladd's Bands''' - are a series of bands crossing the duodenum which can cause duodenal obstruction.

:'''Links:''' [[Gastrointestinal_Tract_-_Abnormalities#Intestinal_Malrotation|Intestinal Malrotation]]

===Intestinal Aganglionosis===

* intestinal aganglionosis, Hirschsprung's disease, aganglionic colon, megacolon, congenital aganglionic megacolon, congenital megacolon
* A condition caused by the lack of enteric nervous system (neural ganglia) in the intestinal tract responsible for gastric motility (peristalsis).

'''MH''' - will cover this topic also in neural crest lecture.

=== Gastroschisis ===
{|
|
* Gastroschisis (omphalocele, paraomphalocele, laparoschisis, abdominoschisis, abdominal hernia)
* congenital abdominal wall defect which results in herniation of fetal abdominal viscera (intestines and/or organs) into the amniotic cavity.
* Incidence of gastroschisis has been reported at 1.66/10,000, occuring more frequently in young mothers (less than 20 years old).
** By definition, it is a body wall defect, not a gastrointestinal tract defect, which in turn impacts upon GIT development.

| [[File:Gastroschisis_01.jpg|150px|link=Ultrasound_-_ Gastroschisis 01]]

:'''Links:''' [[Ultrasound_-_ Gastroschisis 01|Gastroschisis]]
|}

:'''Links:''' [[Gastrointestinal Tract - Abnormalities]]

==Images==
<gallery>

File:Gitbpm.jpg
File:Gray0982a.jpg
File:Gray0982b.jpg
File:Gray0977.jpg
File:Gray0986.jpg
File:Git17mm.jpg
File:Gray0991.jpg
File:Stage14-git.jpg
File:Human_Embryo_17.8mm_GIT.jpg
File:Human_Embryo_17.8mm_a_CNS_GIT.jpg
File:Human_Embryo_17.8mmCNS_GIT.jpg
</gallery>

==UNSW Embryology Links==
{{Template:Gastrointestinal Tract Links}}

==External Links==
{{External Links}}

* '''Embryo Images''' by Drs. Kathleen K. Sulik and Peter R. Bream Jr. notes/images sections on [http://www.med.unc.edu/embryo_images/unit-digest/digest_htms/digesttoc.htm Gut Development]

== Terms ==
'''allantois''' - An extraembryonic membrane, endoderm in origin extension from the early hindgut, then cloaca into the connecting stalk of placental animals, connected to the superior end of developing bladder. In reptiles and birds, acts as a reservoir for wastes and mediates gas exchange. In mammals is associated/incorporated with connecting stalk/placental cord fetal-maternal interface.

'''amnion''' - An extraembryonic membrane]ectoderm and extraembryonic mesoderm in origin and forms the innermost fetal membrane, produces amniotic fluid. This fluid-filled sac initially lies above the trilaminar embryonic disc and with embryoic disc folding this sac is drawn ventrally to enclose (cover) the entire embryo, then fetus. The presence of this membane led to the description of reptiles, bird, and mammals as amniotes.

'''amniotic fluid''' - The fluid that fills amniotic cavity totally encloses and cushions the embryo. Amniotic fluid enters both the gastrointestinal and respiratory tract following rupture of the buccopharyngeal membrane. The late fetus swallows amniotic fluid.

'''buccal''' - (Latin, ''bucca'' = cheek) A term used to relate to the mouth (oral cavity).

'''buccopharyngeal membrane''' - (oral membrane) (Latin, ''bucca'' = cheek) A membrane which forms the external upper membrane limit (cranial end) of the early gastrointestinal tract (GIT). This membrane develops during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm. The membrane lies at the floor of the ventral depression (stomadeum) where the oral cavity will open and will breakdown to form the initial "oral opening" of the gastrointestinal tract. The equivilent membrane at the lower end of the gastrointestinal tract is the cloacal membrane.

'''cloacal membrane''' - Forms the external lower membrane limit (caudal end) of the early gastrointestinal tract (GIT). This membrane is formed during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm. The membrane breaks down to form the initial "anal opening" of the gastrointestinal tract.

'''coelom''' - Term used to describe a space. There are extraembryonic and intraembryonic coeloms that form during vertebrate development. The single intraembryonic coelom will form the 3 major body cavities: pleural, pericardial and peritoneal.

'''foregut''' - The first of the three part/division ('''foregut''' - midgut - hindgut) of the early forming gastrointestinal tract. The foregut runs from the buccopharyngeal membrane to the midgut and forms all the tract (esophagus and stomach) from the oral cavity to beneath the stomach. In addition, a ventral bifurcation of the foregut will also form the respiratory tract epithelium.

'''gastrula''' - (Greek, ''gastrula'' = little stomach) A stage of an animal embryo in which the three germ layers have just formed.

'''gastrulation''' - The process of differentiation forming a gastrula. Term means literally means "to form a gut" but is more in development, as this process converts the bilaminar embryo (epiblast/hypoblast) into the trilaminar embryo ([E.htm#endoderm endoderm]/mesoderm/ectoderm) establishing the 3 germ layers that will form all the future tissues of the entire embryo. This process also establishes the the initial body axes.

'''hindgut''' - The last of the three part/division foregut - midgut - '''hindgut''') of the early forming gastrointestinal tract. The hindgut forms all the tract from the distral transverse colon to the cloacal membrane and extends into the connecting stalk (placental cord) as the allantois. In addition, a ventral of the hindgut will also form the urinary tract (bladder, urethra) epithelium.

'''intraembryonic coelom''' - The "horseshoe-shaped" space (cavity) that forms initially in the third week of development in the lateral plate mesoderm that will eventually form the 3 main body cavities: pericardial, pleural, peritoneal. The intraembryonic coelom communicates transiently with the extraembryonic coelom.

'''neuralation''' - The general term used to describe the early formation of the nervous system. It is often used to describe the early events of differentiation of the central ectoderm region to form the neural plate, then neural groove, then neural tube. The nervous system includes the central nervous system (brain and spinal cord) from the neural tube and the peripheral nervous system (peripheral sensory and sympathetic ganglia) from neural crest. In humans, early neuralation begins in week 3 and continues through week 4.

'''pharynx''' - uppermost end of gastrointestinal and respiratory tract, in the embryo beginning at the buccopharyngeal membrane and forms a major arched cavity within the phrayngeal arches.

'''somitogenesis''' The process of segmentation of the paraxial mesoderm within the trilaminar embryo body to form pairs of somites, or balls of mesoderm. A somite is added either side of the notochord (axial mesoderm) to form a somite pair. The segmentation does not occur in the head region, and begins cranially (head end) and extends caudally (tailward) adding a somite pair at regular time intervals. The process is sequential and therefore used to stage the age of many different species embryos based upon the number visible somite pairs. In humans, the first somite pair appears at day 20 and adds caudally at 1 somite pair/90 minutes until on average 44 pairs eventually form.

'''splanchnic mesoderm''' - Gastrointestinal tract (endoderm) associated mesoderm formed by the separation of the lateral plate mesoderm into two separate components by a cavity, the intraembryonic coelom. Splanchnic mesoderm is the embryonic origin of the gastrointestinal tract connective tissue, smooth muscle, blood vessels and contribute to organ development (pancreas, spleen, liver). The intraembryonic coelom will form the three major body cavities including the space surrounding the gut, the peritoneal cavity. The other half of the lateral plate mesoderm (somatic mesoderm) is associated with the ectoderm of the body wall.

'''stomadeum''' - (stomadeum) A ventral surface depression on the early embryo head surrounding the buccopharyngeal membrane, which lies at the floor of this depression. This surface depression lies between the maxillary and mandibular components of the first pharyngeal arch.

{{Glossary}}

{{Footer}}

[[Category:2012]][[Category:Science-Undergraduate]] [[Category:Gastrointestinal Tract]]

Lecture - Gastrointestinal Development 2013

2013-08-28T06:06:01Z

Z3283213:

=Endoderm Development=
== Introduction ==
[[File:Gray0982a.jpg|thumb|The early developing gastrointestinal tract]]This lecture will cover the early development of the endoderm layer of the trilaminar embryo as it contributes to the lining, glands and organs of the gastrointestinal tract ('''GIT'''). Gastrulation, or gut formation, was historically the easiest observable feature of frog development. In human development, during the 4th week the 3 distinct portions (fore-, mid- and hind-gut) extend the length of the embryo and will contribute different structures. The large mid-gut is generated by lateral embryonic folding which "pinches off" a pocket of the yolk sac, the 2 compartments continue to communicate through the vitelline duct. The oral cavity (mouth) is formed following breakdown of the [[B#buccopharyngeal membrane|buccopharyngeal membrane]] (=oropharyngeal or oral) and the opening means that it contains amniotic fluid, which is also swallowed later in development.

==Lecture Objectives==
[[File:Gray0982b.jpg|thumb|The later developing gastrointestinal tract]]
* Understanding of germ layer contributions to the early gastrointestinal tract (GIT)
* Understanding of the folding of the GIT
* Understanding of three main GIT embryonic divisions
* Understanding of associated organ development (liver, pancreas, spleen)
* Brief understanding of mechanical changes (rotations) during GIT development
* Brief understanding of gastrointestinal abnormalities

{|
Lecture Date: 2013-09-03 Lecture Time: 12:00 Venue: Wallace Wurth LG02 Speaker: Steve Palmer
|}

==Textbooks==

===The Developing Human: Clinically Oriented Embryology===
{|
|-
| [[File:The Developing Human, 9th edn.jpg|90px]]
| '''Citation:''' The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011.
* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00011-4&isbn=978-1-4377-2002-0&uniqId=330028653-2#4-u1.0-B978-1-4377-2002-0..00011-4 Chapter 11 – Alimentary System]
|}

===Larsen's Human Embryology===
{| border='0px'
|-
| [[File:Larsen's human embryology 4th edn.jpg|90px]]
| '''Citation:''' Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009.

* [http://er.library.unsw.edu.au/er/cgi-bin/eraccess.cgi?url=http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06811-9&eid=4-u1.0-B978-0-443-06811-9..10014-4 Chapter 14 - Development of the Gastrointestinal Tract]
|}

===UNSW Embryology===
{|
| [[File:Logo.png|90px]]
| Hill, M.A. (2012) UNSW Embryology (12th ed.). Sydney:UNSW.
{{Gastrointestinal Tract Links}}
|}

==Gastrointestinal Tract Movies==

{{GIT_cartoons}}

{| border='0px'
|-
| {{Gastrointestinal stage 13 movie}}
'''Week 4-5''' [[Carnegie stage 13|Stage 13]]
| {{Gastrointestinal stage 22 movie}}
'''Week 8''' [[Carnegie stage 22|Stage 22]]
|}

== Germ Layer Contributions ==

* '''Endoderm''' - epithelium and associated glands.

* '''Mesoderm''' (splanchnic) - mesentry, connective tissues, smooth muscle, blood vessels.

* '''Ectoderm''' (neural crest) - enteric nervous system.

Both endoderm and mesoderm will contribute to associated organs.

==Week 3-4 Folding==
[[File:Stage11 sagittal.jpg|thumb]]
Folding of the embryonic disc occurs ventrally around the notochord, which forms a rod-like region running rostro-caudally in the midline.

In relation to the notochord:

* '''Laterally''' (either side of the notochord) lies mesoderm.
* '''Rostrally''' (above the notochord end) lies the buccopharyngeal membrane, above this again is the mesoderm region forming the heart.
* '''Caudally''' (below the notochord end) lies the primitive streak (where gastrulation occurred), below this again is the cloacal membrane.
* '''Dorsally''' (above the notochord) lies the neural tube then ectoderm.
* '''Ventrally''' (beneath the notochord) lies the mesoderm then endoderm.

The ventral endoderm (shown yellow) has grown to line a space called the yolk sac. Folding of the embryonic disc "pinches off" part of this yolk sac forming the first primative GIT.

{| border='0px'

|-
| [[File:Endoderm_002_icon.jpg|150px|link=Development_Animation_-_Endoderm]]
| [[File:Amnion 001 icon.jpg|150px|link=Development Animation - Amniotic Cavity]]
| [[File:Stage11_sem100.jpg|150px]]
|-
| [[Development_Animation_-_Endoderm|Endoderm]]
| [[Development Animation - Amniotic Cavity|Yolk Sac]]
| Carnegie stage 11 25 days
|}

The cartoon below is a section through the trunk of the trilaminar embryo showing the further development of the 3 layers and the space (coelom) that forms in the mesoderm (only the righhand side is shown).
{|
| [[File:Mesoderm_cartoon4.gif]]
|
* Within the embryonic disc lateral plate mesoderm a space (coelom) forms, it lies within the embryo and so is called the '''intraembryonic coelom'''.
* This single "horseshoe-shaped" space will form the 3 major body cavities: '''pericardial''' (around the heart), '''pleural''' (around the lungs) and '''peritoneal''' (around the GIT and visceral organs).
** The '''intraembryonic coelom''' also communicates with '''extraembryonic coelom''' (space outside the embryo) through portals (holes) initially on lateral margin of embryonic disc.
* The mesoderm adjacennt to the endoderm is now called the '''splanchnic mesoderm''' which forms the connective tissue and muscular wall of the GIT.
|}
===Buccopharyngeal Membrane===
<gallery>
File:Stage11 sem4.jpg|Stage 11 25 days, Low power ventral view of the Buccopharyngeal Membrane
File:Stage11 sem3.jpg|Higher power ventrolateral view of the Buccopharyngeal Membrane
File:Stage11 sem2.jpg|Close up view of the degenerating Buccopharyngeal Membrane
File:Stage12_sem2.jpg|Stage 12 Week 4, 26 days
File:Stage12 sem9 cloacal membrane.jpg|Stage 12 Cloacal membrane
</gallery>

== Week 5-6 Canalization ==
{| border='0px'

|-
| [[File:Gastrointestinal tract growth 01 icon.jpg|150px|link=Development Animation - Gastrointestinal Tract Growth]]
|
* Beginning at week 5 endoderm in the GIT wall proliferates
* Totally blocking (occluding) the lumen by week 6
* Over the next two weeks this tissue degenerates reforming a hollow gut tube.
* The process is called recanalization (hollow, then solid, then hollow again), abnormalities in this process can lead to duplications or stenosis.
* By the end of week 8 the GIT endoderm tube is a tube once more.

|-
| [[Development Animation - Gastrointestinal Tract Growth|Tract Growth]]
|
|}
== Gastrointestinal Tract Divisions ==
{|
|
* During the 4th week the 3 distinct portions (fore-, mid- and hind-gut) extend the length of the embryo and will contribute different components of the GIT.
* These 3 divisions are also later defined by the vascular (artery) supply to each of theses divisions.
* The large '''mid-gut''' is generated by lateral embryonic folding which "pinches off" a pocket of the yolk sac, the 2 compartments continue to communicate through the vitelline duct.
* The '''oral cavity''' ('''mouth''') is formed
** following breakdown of the buccopharyngeal membrane (oropharyngeal, oral membrane)
** contributed to mainly by the pharynx lying within the pharyngeal arches.
** opening of the GIT means that it contains amniotic fluid, which is also swallowed later in development.
| [[File:GIT_blood_supply.jpg|300px]]
|}

===Foregut===
{|
|
* Oral cavity
* Pharynx (esophagus, trachea)
** Respiratory tract (a ventral bud arising at this level, covered in next lecture).
* Stomach
* Duodenum

| [[File:Gitbpm.jpg]]

Stage 11 foregut
|}

===Midgut===

{|
|
* Starting at part of the duodenum, ileum (small intestine), jejunum, and part of the colon (large intestine).
* Much of the '''midgut is herniated''' at the umbilicus external to the abdomen through development. A key step in development is the rotation of this midgut that must occur to place the GIT in the correct abdominal position with its associated mesentry.
* The '''mesentries''' of the GIT are generated from the common '''dorsal mesentry''', with the ventral mesentry contributing to the '''lesser omentum''' and '''falciform ligament'''.

| [[File:Gray0986.jpg|200px]]

midgut herniation
|}

===Hindgut===
* Forms the - distral transverse colon, descending colon, sigmoid colon, rectum and cloaca.
* The '''cloaca''' is the common urogenital sinus which will later become divided (partitioned) into an anterior urogenital and posterior GIT rectal component.

== Stage 13 ==
* The images below provide an overview of the mid-embryonic period (end week 4) [[Carnegie stage 13|stage 13]] embryo gastrointestinal tract.
* This will be covered in detain in this week's laboratory.

[[File:Stage14-git.jpg|600px]]

==Stomach==
[[File:Stage14 stomach.jpg|thumb]]
* During week 4 where the stomach will form the GIT tube begins to dilate (forming an enlarged lumen in the tube).
* Dorsal border grows more rapidly than ventral (establishes the greater curvature of the stomach).
* A second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.

[[File:Human Embryo 17.8mm GIT.jpg|400px]]

Stomach, Week 7, Stage 19

:'''Links:''' [[Gastrointestinal Tract - Stomach Development|Stomach Development]]

===Greater Omentum===
[[File:Greater-omentum.jpg|thumb]]
* The greater omentum hangs like an apron over the small intestine and transverse colon.
* It begins attached to the inferior end of the stomach as a fold of the dorsal mesogastrium which later fuses to form the structure we recognise anatomically.
* The figure shows a lateral view of this process comparing the early second trimester arrangement with the newborn structure.

{| border='0px'

|-
| [[File:Greater_omentum_001_icon.jpg|150px|link=Development_Animation_-_Greater_Omentum]]
| [[File:Lesser sac_01_icon.jpg|150px|link=Development_Animation_-_Lesser_Sac]]
|-
| [[Development_Animation_-_Greater_Omentum|Greater Omentum]]
| [[Development_Animation_-_Lesser_Sac|Lesser Sac]]
|-
|}

===Duodenum/Pancreas Rotation===
{|
|
* After the stomach the initial portion of the GIT tube is the duodenum which initially lies in the midline within the peritoneal cavity
* duodenum along with the attached pancreas undergoes rotation
* also incorporated into the body wall to become a retroperitoneal structure.
| [[File:Pancreas_rotation.jpg|300px]]

The diagram shows this rotation with spinal cord at the top, vertebral body then dorsal aorta then pertioneal wall and cavity.
|}

== Midgut ==
* Midgut (intestine) is initially continuous with the yolk sac (externally)
* The connection narrows becoming a "yolk stalk" (and finally lost altogether).
* Initial growth of the midgut forms a loop extending outside the ventral body wall.
* Continued growth occurs outside the body wall (herniated)
* Growth leads to a series of rotates (establishing the adult anatomy)

[[File:Gray0986.jpg|200px|midgut herniation]] [[File:Normal intestinal rotation cartoon.jpg|400px]]

:'''Links:''' [[Gastrointestinal_Tract_-_Intestine_Development|Intestine Development]]

== Gastrointestinal Tract Associated Organs ==

===Liver===
[[File:Stage_22_image_182.jpg|thumb|Liver week 8 stage 22 embryo]]
* The transverse septum (septum transversum) arises at an embryonic junctional site.
** junctional region externally is where the ectoderm of the amnion meets the endoderm of the yolk sac.
** junctional region internally is where the foregut meets the midgut.
* The mesenchymal structure of the transverse septum provides a support within which both blood vessels and the liver begin to form.
** Hepatic Buds - form hepatocytes, produce bile from week 13 (forms meconium of newborn)
** Vitelline Veins - form sinusoids
** Mesenchyme - form connective tissue and Kupffer cells
* Embryonic functions:
** Vascular junction region (placenta, vitelline, systemic)
** Haematopoiesis - location of blood stem cells until bone marrow development.

<gallery>
File:Histology-fetal liver HEx40.jpg|Histology-fetal liver HEx40
File:Histology-fetal_liver_HEx100.jpg|Histology-fetal liver x100
</gallery>
[[File:Liver_structure_cartoon.jpg|thumb|Adult liver structure]]

:'''Links:''' [[Gastrointestinal Tract - Liver Development|Liver Development]]

===Spleen===
[[File:Stage 22 image 087.jpg|thumb|Spleen week 8 stage 22 embryo]]
* Mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas.
* The spleen is located on the left side of the abdomen and has a role initially in blood and then immune system development.
* The spleen's haematopoietic function (blood cell formation) is lost with embryo development and lymphoid precursor cells migrate into the developing organ.
* Vascularization of the spleen arises initially by branches from the dorsal aorta.

{|
| [[File:Lesser sac_01_icon.jpg|200px|link=Development_Animation_-_Lesser_Sac]]
|
'''Legend'''
* '''spleen in mesentery'''
* '''stomach endoderm of gastrointestinal tract'''
* '''liver'''
* '''mesentery'''
|}

:'''Links:''' [[Cardiovascular System - Spleen Development|Spleen Development]]

===Pancreas===
[[File:Stage22 pancreas a.jpg|thumb|Pancreas, week 8 stage 22]]
* At the foregut/midgut junction the septum transversum generates 2 pancreatic buds (dorsal and ventral endoderm) which will fuse to form the pancreas.
* The '''dorsal bud''' arises first and generates most of the pancreas.
* The '''ventral bud''' arises beside the bile duct and forms only part of the head and uncinate process of the pancreas.
* functions - '''exocrine''' and '''endocrine''' (endocrine development will be covered in a later lecture).
[[File:Pancreatic_duct_developing.jpg|300px]] [[File:Mouse-pancreas duct formation.jpg|300px]]

:'''Links:''' [[Gastrointestinal Tract - Pancreas Development|Exocrine Pancreas]] | [[Endocrine - Pancreas Development|Endocrine Pancreas]]

== Gastrointestinal Tract Abnormalities ==
[[File:Meckel%27s_diverticulum_01.jpg|thumb|Meckel's Diverticulum]]
===Lumen Abnormalities===
There are several types of abnormalities that impact upon the continuity of the gastrointestinal tract lumen.

* '''Atresia''' - interuption of the lumen (esophageal atresia, duodenal atresia, extrahepatic biliary atresia, anorectal atresia)
* '''Stenosis''' - narrowing of the lumen (duodenal stenosis, pyloric stenosis).
* '''Duplication''' - incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis.

[[File:Gastrointestinal_tract_duplication_sites.jpg|200px]]

===Meckel's Diverticulum===

* most common gastrointestinal tract abnormality
* results from improper closure and absorption of the omphalomesenteric duct (vitelline duct) in development.
** Transient developmental duct connects the yolk to the primitive GIT.

===Intestinal Malrotation===
[[File:Intestinal_malrotation.jpg|thumb|Intestinal malrotation]]
Presents clinically in symptomatic malrotation as:

* Neonates - bilious vomiting and bloody stools.
* Newborn - bilious vomiting and failure to thrive.
* Infants - recurrent abdominal pain, intestinal obstruction, malabsorption/diarrhea, peritonitis/septic shock, solid food intolerance, common bile duct obstruction, abdominal distention, and failure to thrive.

'''Ladd's Bands''' - are a series of bands crossing the duodenum which can cause duodenal obstruction.

:'''Links:''' [[Gastrointestinal_Tract_-_Abnormalities#Intestinal_Malrotation|Intestinal Malrotation]]

===Intestinal Aganglionosis===

* intestinal aganglionosis, Hirschsprung's disease, aganglionic colon, megacolon, congenital aganglionic megacolon, congenital megacolon
* A condition caused by the lack of enteric nervous system (neural ganglia) in the intestinal tract responsible for gastric motility (peristalsis).

'''MH''' - will cover this topic also in neural crest lecture.

=== Gastroschisis ===
{|
|
* Gastroschisis (omphalocele, paraomphalocele, laparoschisis, abdominoschisis, abdominal hernia)
* congenital abdominal wall defect which results in herniation of fetal abdominal viscera (intestines and/or organs) into the amniotic cavity.
* Incidence of gastroschisis has been reported at 1.66/10,000, occuring more frequently in young mothers (less than 20 years old).
** By definition, it is a body wall defect, not a gastrointestinal tract defect, which in turn impacts upon GIT development.

| [[File:Gastroschisis_01.jpg|150px|link=Ultrasound_-_ Gastroschisis 01]]

:'''Links:''' [[Ultrasound_-_ Gastroschisis 01|Gastroschisis]]
|}

:'''Links:''' [[Gastrointestinal Tract - Abnormalities]]

==Images==
<gallery>

File:Gitbpm.jpg
File:Gray0982a.jpg
File:Gray0982b.jpg
File:Gray0977.jpg
File:Gray0986.jpg
File:Git17mm.jpg
File:Gray0991.jpg
File:Stage14-git.jpg
File:Human_Embryo_17.8mm_GIT.jpg
File:Human_Embryo_17.8mm_a_CNS_GIT.jpg
File:Human_Embryo_17.8mmCNS_GIT.jpg
</gallery>

==UNSW Embryology Links==
{{Template:Gastrointestinal Tract Links}}

==External Links==
{{External Links}}

* '''Embryo Images''' by Drs. Kathleen K. Sulik and Peter R. Bream Jr. notes/images sections on [http://www.med.unc.edu/embryo_images/unit-digest/digest_htms/digesttoc.htm Gut Development]

== Terms ==
'''allantois''' - An extraembryonic membrane, endoderm in origin extension from the early hindgut, then cloaca into the connecting stalk of placental animals, connected to the superior end of developing bladder. In reptiles and birds, acts as a reservoir for wastes and mediates gas exchange. In mammals is associated/incorporated with connecting stalk/placental cord fetal-maternal interface.

'''amnion''' - An extraembryonic membrane]ectoderm and extraembryonic mesoderm in origin and forms the innermost fetal membrane, produces amniotic fluid. This fluid-filled sac initially lies above the trilaminar embryonic disc and with embryoic disc folding this sac is drawn ventrally to enclose (cover) the entire embryo, then fetus. The presence of this membane led to the description of reptiles, bird, and mammals as amniotes.

'''amniotic fluid''' - The fluid that fills amniotic cavity totally encloses and cushions the embryo. Amniotic fluid enters both the gastrointestinal and respiratory tract following rupture of the buccopharyngeal membrane. The late fetus swallows amniotic fluid.

'''buccal''' - (Latin, ''bucca'' = cheek) A term used to relate to the mouth (oral cavity).

'''buccopharyngeal membrane''' - (oral membrane) (Latin, ''bucca'' = cheek) A membrane which forms the external upper membrane limit (cranial end) of the early gastrointestinal tract (GIT). This membrane develops during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm. The membrane lies at the floor of the ventral depression (stomadeum) where the oral cavity will open and will breakdown to form the initial "oral opening" of the gastrointestinal tract. The equivilent membrane at the lower end of the gastrointestinal tract is the cloacal membrane.

'''cloacal membrane''' - Forms the external lower membrane limit (caudal end) of the early gastrointestinal tract (GIT). This membrane is formed during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm. The membrane breaks down to form the initial "anal opening" of the gastrointestinal tract.

'''coelom''' - Term used to describe a space. There are extraembryonic and intraembryonic coeloms that form during vertebrate development. The single intraembryonic coelom will form the 3 major body cavities: pleural, pericardial and peritoneal.

'''foregut''' - The first of the three part/division ('''foregut''' - midgut - hindgut) of the early forming gastrointestinal tract. The foregut runs from the buccopharyngeal membrane to the midgut and forms all the tract (esophagus and stomach) from the oral cavity to beneath the stomach. In addition, a ventral bifurcation of the foregut will also form the respiratory tract epithelium.

'''gastrula''' - (Greek, ''gastrula'' = little stomach) A stage of an animal embryo in which the three germ layers have just formed.

'''gastrulation''' - The process of differentiation forming a gastrula. Term means literally means "to form a gut" but is more in development, as this process converts the bilaminar embryo (epiblast/hypoblast) into the trilaminar embryo ([E.htm#endoderm endoderm]/mesoderm/ectoderm) establishing the 3 germ layers that will form all the future tissues of the entire embryo. This process also establishes the the initial body axes.

'''hindgut''' - The last of the three part/division foregut - midgut - '''hindgut''') of the early forming gastrointestinal tract. The hindgut forms all the tract from the distral transverse colon to the cloacal membrane and extends into the connecting stalk (placental cord) as the allantois. In addition, a ventral of the hindgut will also form the urinary tract (bladder, urethra) epithelium.

'''intraembryonic coelom''' - The "horseshoe-shaped" space (cavity) that forms initially in the third week of development in the lateral plate mesoderm that will eventually form the 3 main body cavities: pericardial, pleural, peritoneal. The intraembryonic coelom communicates transiently with the extraembryonic coelom.

'''neuralation''' - The general term used to describe the early formation of the nervous system. It is often used to describe the early events of differentiation of the central ectoderm region to form the neural plate, then neural groove, then neural tube. The nervous system includes the central nervous system (brain and spinal cord) from the neural tube and the peripheral nervous system (peripheral sensory and sympathetic ganglia) from neural crest. In humans, early neuralation begins in week 3 and continues through week 4.

'''pharynx''' - uppermost end of gastrointestinal and respiratory tract, in the embryo beginning at the buccopharyngeal membrane and forms a major arched cavity within the phrayngeal arches.

'''somitogenesis''' The process of segmentation of the paraxial mesoderm within the trilaminar embryo body to form pairs of somites, or balls of mesoderm. A somite is added either side of the notochord (axial mesoderm) to form a somite pair. The segmentation does not occur in the head region, and begins cranially (head end) and extends caudally (tailward) adding a somite pair at regular time intervals. The process is sequential and therefore used to stage the age of many different species embryos based upon the number visible somite pairs. In humans, the first somite pair appears at day 20 and adds caudally at 1 somite pair/90 minutes until on average 44 pairs eventually form.

'''splanchnic mesoderm''' - Gastrointestinal tract (endoderm) associated mesoderm formed by the separation of the lateral plate mesoderm into two separate components by a cavity, the intraembryonic coelom. Splanchnic mesoderm is the embryonic origin of the gastrointestinal tract connective tissue, smooth muscle, blood vessels and contribute to organ development (pancreas, spleen, liver). The intraembryonic coelom will form the three major body cavities including the space surrounding the gut, the peritoneal cavity. The other half of the lateral plate mesoderm (somatic mesoderm) is associated with the ectoderm of the body wall.

'''stomadeum''' - (stomadeum) A ventral surface depression on the early embryo head surrounding the buccopharyngeal membrane, which lies at the floor of this depression. This surface depression lies between the maxillary and mandibular components of the first pharyngeal arch.

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[[Category:2012]][[Category:Science-Undergraduate]] [[Category:Gastrointestinal Tract]]